@article {pmid42177211,
year = {2026},
author = {Sheikh, S and Shadin, M and Eity, TA and Oni, MIJ and Khatun, MM and Chowdhury, R and Bhuia, MS and Alfaifi, M and Altemani, FH and Altemani, AH and Saleh, N and Islam, MT},
title = {Lenalidomide ameliorates cognitive impairment via putative AChE inhibition: an in silico and in vivo study in a scopolamine-induced cognitive impairment model.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-49461-8},
pmid = {42177211},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) causes progressive cognitive decline, and current therapies provide limited benefit. This study evaluated the neuroprotective effects of lenalidomide (LLM), a thalidomide derivative, in a scopolamine-induced mouse model of cognitive impairment, with emphasis on its acetylcholinesterase (AChE) inhibitory potential. Mice received LLM (5, 10, and 20 mg/kg), donepezil (DNP) (3 mg/kg), or a combination and were assessed using Y-maze, passive avoidance, novel object recognition, and Morris water maze tests. In silico analysis, including molecular docking, 100 ns molecular dynamics simulation and ADMET profiling were performed to investigate the interaction of LLM with AChE. Memory performance showed a significant and dose-dependent improvement after the treatment of LLM. The 20 mg/kg dose exhibited effects comparable to DNP. LLM and DNP work together to increase effectiveness. Docking and simulation analyses revealed strong, stable binding to AChE while ADMET values indicated good drug-likeness. LLM exhibits neuroprotective and cognition enhancing effects in the scopolamine-induced model. In silico study also shows its potential as an AChE inhibitor. The study's anti-inflammatory mechanisms might also be helpful but need more exploration.},
}

@article {pmid42177528,
year = {2026},
author = {Chen, L and Lin, X and Fu, M and Chen, S and Yan, Z and Diao, Y and Chen, G and Huang, Z and Sun, Y and Lin, Y and Ye, Z and Zhou, Y and Ye, Q},
title = {Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04552-6},
pmid = {42177528},
issn = {1477-3155},
support = {2023XH023//the Postdoctoral Research Project Startup Fund of Fujian Medical University Union Hospital/ ; 2024QH2020//the Startup Fund for Scientific Research of Fujian Medical University/ ; 2023Y9008//the Joint Funds for the Innovation of Science and Technology, Fujian Province/ ; 2024ZD01002//the Major Special Project of Fujian Provincial Health Technology Project/ ; U23A20423//the National Natural Science Foundation of China/ ; 2022Y2005//the Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province/ ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A hallmark pathological feature of PD is the abnormal aggregation of α-synuclein (αSyn) into insoluble Lewy bodies. Consequently, developing strategies to inhibit αSyn aggregation in the brain has been a major research focus for PD treatment. This study developed a therapeutic approach using engineered neuronal exosomes. These exosomes were modified to extend their blood circulation half-life to 3.8 h and enhance targeting, with a 2.15 ± 0.09% brain signal proportion (vs. 0.78 ± 0.07% for free dye). They were then loaded with a self-developed αSyn aggregation-blocking peptide (sPep) as well as the antioxidant pyrroloquinoline quinone (PQQ). We investigated the therapeutic efficacy of this system in both in vitro and in vivo models of PD. Our experiments confirmed that the screened sPep effectively targeted and blocked αSyn aggregation both in vitro and in vivo. Neuronal exosomes, isolated by ultracentrifugation and hybridization, demonstrated strong abilities to cross the blood-brain barrier. In vivo studies revealed that the treatment significantly improved motor and cognitive functions in PD model mice. The underlying neuroprotective mechanisms included reducing αSyn aggregation, enhancing antioxidant capacity, ameliorating mitochondrial dysfunction, and suppressing cell apoptosis, collectively promoting the survival of dopaminergic neurons. These findings demonstrate that the engineered exosome-mediated delivery system exerts a protective effect against PD pathology.},
}

@article {pmid42178013,
year = {2026},
author = {Pattanaik, S and Sahu, PK and Paidesetty, SK and Prusty, SK and Pakeeraiah, K and Panda, PK and Lopamudra, },
title = {Design, synthesis, and inhibition of oxidative, amyloidogenic, and cholinergic dysfunction of Saxagliptin-derived Schiff bases against STZ-induced sporadic AD-like pathology.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178987},
doi = {10.1016/j.ejphar.2026.178987},
pmid = {42178013},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) shares significant pathological convergence with diabetes, primarily through insulin resistance. This leads to oxidative stress, neuronal inflammation, plaque formation, cholinergic dysfunction, and impaired neuronal survival. Herein, we report 10 Saxagliptin (SXG, a potent DPP-IV inhibitor)-derived Schiff base derivatives that were virtually designed and screened. Five leads were prioritized using ADMET profiling and molecular docking, then synthesized via Schiff base condensation with selected aryl aldehydes to target AD progression associated with diabetes. Structural integrity, redox activity, and stability were confirmed by comprehensive characterization, including chromatographic and spectroscopic analyses, DFT calculations, and in vitro antioxidant assays. Neuroprotective potential was thus assessed in vivo by inducing AD-like pathology in rats with a single i.p. dose of STZ at 45 mg/kg, thereby reproducing brain insulin resistance, oxidative-nitrosative stress, and cholinergic dysfunction. Significant neurodegeneration in STZ-treated rats was evidenced by behavioral analyses, biochemical markers (AChE, Aβ42), oxidative stress indices (SOD, CAT, GSH, GPx, MDA, NO, MPO), and hippocampal histology. Treatment with SXG and derivatives at 0.5 mg/kg, orally, resulted in significant restoration of antioxidant defenses, inhibition of lipid peroxidation and NO overproduction, reduction of inflammatory oxidative bursts, and improved cognition in treated groups. Remarkably, derivatives 3c and 3e showed superior free-radical scavenging and greater regulation of redox biomarkers, which were associated with healthy, defined hippocampal cytoarchitecture and reduced neuronal pyknosis and necrosis compared with SXG. Additionally, 3e showed strong therapeutic efficacy by targeting oxidative stress, cholinergic, and amyloidogenic pathways synchronously.},
}

@article {pmid42178051,
year = {2026},
author = {Wang, C and Liu, J and Zhou, Y and Shan, X and Li, S and Ding, S and Zhuo, X and Li, Q and Yang, W and Zhang, X and Gu, L},
title = {Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118103},
doi = {10.1016/j.bcp.2026.118103},
pmid = {42178051},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic, low-grade inflammatory neurodegenerative disorder. Inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a potential therapeutic strategy for AD, but no approved NLRP3-specific inhibitors are available for clinical use, and current agents often cause significant side effects despite their anti-inflammatory benefits. Acacetin, is a flavonoid compound that can penetrate the blood-brain barrier, with potential for treating AD.The purpose of this study is to clarify the relationship between the anti-AD effect of acacetin and its mechanism of inhibiting NLRP3.acacetin improved cognitive function and reduced neuronal damage in 3xTg mice. Further Acacetin directly binds to sorting nexin-5 (SNX5) and upregulates its expression. This, in turn, activates autophagy to degrade the NLRP3 inflammasome, alleviates inflammationin HT22 cells and BV2 cells. These findings suggest that Acacetin can exert an anti-AD effect by targeting SNX5 to activate autophagy and promote the degradation of the NLRP3 inflammasome, which underscore the importance of targeting SNX5 to suppress NLRP3 inflammasome activation in AD treatment.},
}

@article {pmid42178053,
year = {2026},
author = {Elkabes, S},
title = {Sexually dimorphic roles of toll-like receptors in the central nervous system.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106830},
doi = {10.1016/j.bbi.2026.106830},
pmid = {42178053},
issn = {1090-2139},
abstract = {Many neurological and psychiatric diseases and disorders show sex differences in prevalence, incidence, disease manifestation and response to treatment. Yet, historically, most clinical and pre-clinical studies have been conducted disproportionately or exclusively in male subjects. In recent years, this research bias has been increasingly addressed through human and animal studies where both sexes are appropriately represented. These investigations have identified sex-specific disease mechanisms driven by a combination of distinct genetic, anatomical, physiological, hormonal and neural factors in males and females. Sexual dimorphism in immune function has long been recognized. Toll-like receptors (TLRs), important mediators of the innate immune response to pathogens and endogenous danger signals, play sex-biased roles in peripheral immunity. Toll-like receptors are also expressed in cells intrinsic to the central nervous system (CNS). They initiate, not only neuroinflammation in CNS infections and disease and injuries, but also influence neurodevelopment and normal aging. Emerging evidence indicates that TLRs expressed in CNS cells contribute to neural pathology in a sex-specific manner, a research area that warrants further investigations. The aim of the present review is to highlight the sex-specific contribution of TLRs expressed in the CNS to chronic pain, neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's Disease and psychiatric disorders including major depressive disorder (MDD). Major findings are highlighted, essential concepts, controversies and knowledge gaps are discussed, and potential future directions are proposed. Attention is drawn to the importance of advancing this research area given that neuroinflammation is a key player in many CNS pathologies and TLRs are the essential drivers of neuroinflammation.},
}

@article {pmid42178337,
year = {2026},
author = {Abaspour, N and Roghani, M and Bagheri, M and Khalili, M},
title = {Pioglitazone protects against trimethyltin hippocampal injury by reducing pyroptosis, mitochondrial dysregulation and ER stress.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54103-0},
pmid = {42178337},
issn = {2045-2322},
support = {522458//shahed University/ ; },
abstract = {Hippocampus-specific neurotoxic trimethyltin (TMT) is routinely used to mimic a reliable murine phenotype of neurodegeneration as well as cognitive loss and is accordingly appropriate to analyze pathogenesis of the prevalent neurodegenerative disorders, i.e. Alzheimer's disease (AD), and to examine the effectiveness of novel therapeutics. Antidiabetic medication pioglitazone has exhibited neuroprotective effects with promising clinical indications for neurodegeneration-based illnesses. This study was accomplished for studying the neuroprotective effect of pioglitazone against TMT-initiated cognitive decline and allied hippocampal neurodegeneration. For this purpose, rats received intraperitoneal TMT (8 mg/kg) to generate a model of AD-like neurodegeneration and subsequently had oral daily administration of pioglitazone for 3 weeks (20 mg/kg). The acetylcholinesterase inhibitor and certified anti-AD drug donepezil (4 mg/kg) was similarly used as a positive control medicine. Pioglitazone treatment was accompanied by lower cognitive deficits in novel object recognition test and Barnes maze paradigm in addition to mitigation of astrogliosis severity with glial fibrillary acidic protein (GFAP) as its specific indicator and lower CA1 neuronal loss. Furthermore, pioglitazone partially normalized hippocampal factors of oxidative stress and neuroinflammation together with downregulation of pyroptotic parameters comprising caspase 1 and NLR family pyrin domain containing 3 (NLRP3). Moreover, less activity of acetylcholinesterase (AChE) and greater quantity of mitochondrial health-allied factors comprising peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial membrane potential (MMP), mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ (PPARγ) were likewise detected after pioglitazone treatment. These advantageous properties of pioglitazone were accompanied by inferior quantity of specific AD-allied markers comprising presenilin1 (PSEN1) and hyperphosphorylated tau (p-tau) as well as downregulation of endoplasmic reticulum (ER) stress, as observed by lower levels of PKR-like ER kinase (PERK), C/EBP homologous protein (CHOP), glucose-regulated protein 78 (GRP78), and inositol-requiring enzyme 1α (IRE1α). While anti-AD donepezil treatment was associated with improvement of cognitive function, however, it was not capable to significantly yield most advantageous effects of anti-diabetic PPARg agonist pioglitazone. This study disclosed the underlying pathways for neuroprotective effect of pioglitazone in TMT neurodegeneration and AD-like phenotype.},
}

@article {pmid42178577,
year = {2026},
author = {Ruthirakuhan, M and Mills, M and Rosenberg, P and Haughey, N and Mintzer, J and Craft, S and Herrmann, N and Lerner, AJ and Levey, AI and Padala, PR and Porsteinsson, A and van Dyck, CH and Shade, D and Lanctôt, KL},
title = {Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02055-y},
pmid = {42178577},
issn = {1758-9193},
support = {R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; R01 AG046543/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Apathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

METHODS: Participants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

RESULTS: Of the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

CONCLUSIONS: This study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.},
}

@article {pmid42178732,
year = {2026},
author = {Liu, C and Qin, X and Talisa, VB and Wang, J},
title = {Heterogeneous causal mediation analysis using Bayesian additive regression trees.},
journal = {Biometrics},
volume = {82},
number = {2},
pages = {},
doi = {10.1093/biomtc/ujag079},
pmid = {42178732},
issn = {1541-0420},
support = {R21AG087057/NH/NIH HHS/United States ; R01AG080590/NH/NIH HHS/United States ; S10OD028483/NH/NIH HHS/United States ; 2337612//National Science Foundation Faculty Early Career Development Program (CAREER) Award/ ; R305D200031//U.S. Department of Education Institute of Education Sciences Grant/ ; },
mesh = {Bayes Theorem ; Humans ; Computer Simulation ; Alzheimer Disease/genetics/pathology ; Regression Analysis ; *Causality ; *Mediation Analysis ; Apolipoproteins E/genetics ; Models, Statistical ; Genotype ; Biometry/methods ; Cognition ; },
abstract = {Causal mediation analysis provides insights into the mechanisms through which treatments affect outcomes. While mediation effects often vary across individuals, most existing methods focus solely on population-average effects, overlooking individual-level heterogeneity. To address this limitation, we propose a Bayesian regression tree ensemble method that flexibly models nonlinear relationships and captures treatment-by-mediator interactions in the mediation process. Using hierarchical posterior sampling, our approach provides credible intervals with nominal coverage rates for inferring heterogeneous mediation effects. Additionally, we leverage regression tree summaries to identify subgroups with distinct mediation effects and employ SHapley Additive exPlanation values to highlight key moderators and their influence on the mediation process. Comprehensive simulations demonstrate the method's accuracy in estimating and inferring heterogeneous mediation effects. Finally, we apply our method to investigate the heterogeneous mediation role of Alzheimer's disease pathology burden in the effect of apolipoprotein E genotype on late-life cognition.},
}

Bayes Theorem
Humans
Computer Simulation
Alzheimer Disease/genetics/pathology
Regression Analysis
*Causality
*Mediation Analysis
Apolipoproteins E/genetics
Models, Statistical
Genotype
Biometry/methods
Cognition

@article {pmid42179062,
year = {2026},
author = {Li, D and Dai, W and Li, X and Li, H and Li, L and Zhao, Y and Wang, X and Zhang, L},
title = {Amyloid-β suppresses oligodendrocyte differentiation in adult oligodendrocyte precursor cells (OPCs), with inflammatory gene changes distinguishing it from developmental OPCs.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261451403},
doi = {10.1177/13872877261451403},
pmid = {42179062},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) involves white matter deterioration, but how amyloid-β (Aβ) affects oligodendrocyte lineage cells at different maturation stages remains unclear.ObjectiveTo determine whether Aβ impairs oligodendrocyte differentiation and myelination in adult oligodendrocyte precursor cells (OPCs) and to identify molecular correlates via RNA-seq.MethodsOligodendrocyte lineage cells were examined in plaque-associated regions of 8-month-old 5x familial Alzheimer's disease (FAD) mice by immunohistochemistry. Primary OPCs from neonatal and adult rats were cultured with or without amyloid-β1-42 oligomers (oAβ42) to assess differentiation. Myelination was evaluated in organotypic slice cultures. RNA-seq and qPCR were performed to identify oAβ42-induced gene expression changes.ResultsIn 5xFAD mice, Olig2[+] cells were reduced near plaques, with CC1[+] mature oligodendrocytes showing a pronounced decrease, while PDGFRα[+] OPCs remained unchanged. In vitro, oAβ42 inhibited differentiation of both neonatal and adult OPCs, with adult OPCs exhibiting intrinsically slower maturation. Slice cultures revealed selective hypomyelination (reduced myelin basic protein) after oAβ42 treatment. RNA-seq showed that oAβ42 induced a distinct transcriptomic profile in adult OPCs, with upregulated genes enriched in immune/inflammatory pathways. Core inflammatory genes Nr4a1 and Tnf were significantly upregulated, validated by qPCR.ConclusionsoAβ42 plaque pathology is associated with oligodendrocyte maturation blockade. Aβ impairs OPC differentiation in purified cultures accompanied by inflammatory transcriptional changes. These findings highlight oligodendrocyte dysfunction in AD white matter pathology and reveal a specific oAβ42 response in adult OPCs.},
}

@article {pmid42179084,
year = {2026},
author = {Kim, D and Jeong, H and Lim, HK and Ahn, SM and Song, M},
title = {Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261450638},
doi = {10.1177/13872877261450638},
pmid = {42179084},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.},
}

@article {pmid42179740,
year = {2026},
author = {Chen, R and Chiu, SY and DeSimone, JC and Wang, WE and Barmpoutis, A and Mcmillan, CT and Radhakrishnan, H and Irwin, DJ and Clark, L and Kantarci, K and Boeve, BF and Vaillancourt, DE},
title = {Automated Imaging Differentiation for Dementia: Including Alzheimer Disease Dementia and Dementia with Lewy Bodies.},
journal = {Neurology open access},
volume = {2},
number = {2},
pages = {},
pmid = {42179740},
issn = {2998-7601},
abstract = {BACKGROUND AND OBJECTIVES: Differentiation of Alzheimer's disease dementia (ADD) and dementia with Lewy bodies (DLB) remains a challenge. Free-water imaging has been investigated in neurodegenerative diseases and was found to be associated with neurodegeneration and neuroinflammation. This retrospective cohort study tested whether Automated Imaging Differentiation for Dementia (AIDD), combining diffusion free-water imaging (FWI) and support vector machine, predicts ADD vs DLB with high accuracy.

METHODS: Diffusion MRI data was rendered from ADNI, NACC, and PDBP. Free-water and free-water corrected fractional anisotropy were calculated for each participant using a bi-tensor model. Diffusion metrics were randomly assigned to training and testing sets. The primary outcome was the area under the curve (AUC) in the test set. AIDD was paired with antemortem MRI to predict postmortem pathology.

RESULTS: A total of 519 diffusion scans were processed with 258 ADD (mean age 73.7 (8.8), 50% male), 129 DLB (mean age 69.3, 88% male), and 132 controls (mean age 73.6 (6.8), 40% male). The machine learning sample included 387 scans,129 ADD with a mean age of 72.8 (8.7), 52.7% male; 129 DLB with a mean age of 69.3 (8.1), 87.6% male; and 129 controls with a mean age of 73.7 (6.8), 39.5% male). AIDD showed high training AUC for ADD vs DLB = 0.995 (95% CI, 0.985-1.000), ADD vs controls = 0.992 (95% CI, 0.982-1.000), DLB vs controls = 0.991 (95% CI, 0.983-0.999), and controls vs ADD/DLB = 0.990 (95% CI, 0.979-1.000). The testing AUCs were similar: ADD vs DLB = 0.995, ADD vs controls = 0.958, DLB vs controls = 0.939, controls vs ADD/DLB = 0.903. AIDD predictions were confirmed pathologically in a cohort of 13 patients.

DISCUSSION: This study demonstrates that machine learning in combination with free-water imaging can differentiate ADD, DLB, and normal aging with high clinical and pathological accuracy. Advancement in early detection of dementia can lead to more appropriate treatment plans, especially for DLB, and improved disease stratification that have hindered drug development trials.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that Automated Imaging Differentiation for Dementia, combining diffusion free-water imaging and machine learning accurately distinguishes Alzheimer's Disease from Dementia with Lewy bodies.},
}

@article {pmid42179743,
year = {2026},
author = {Yu, Z and Li, H and Wang, Y and Shen, F and Wang, Y},
title = {Aerobic exercise versus acupuncture as adjuncts to acetylcholinesterase inhibitors in Alzheimer's disease: a systematic review and Bayesian network meta-analysis.},
journal = {American journal of clinical and experimental immunology},
volume = {15},
number = {2},
pages = {37-49},
pmid = {42179743},
issn = {2164-7712},
abstract = {Acetylcholinesterase inhibitors (AChEIs) remain the standard therapy for Alzheimer's disease (AD), yet their cognitive and functional benefits are limited, creating a strong need for effective adjunctive treatments. Aerobic exercise and acupuncture have been proposed as promising complements to AChEIs because of their potentially synergistic neurotrophic and cholinergic effects. To compare these treatment combinations, we carried out a Bayesian network meta-analysis (BNMA) of randomized controlled trials (RCTs). These studies were sourced from major English and Chinese databases and examined cognitive and functional outcomes. In total, 37 RCTs were included, covering 2,188 participants. Among all, combined acupuncture (SUCRA = 78.92%) and fire needle therapy (SUCRA = 78%) demonstrated the highest probability of improving Mini Mental State Examination scores, while moderate intensity aerobic exercise ranked best for the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, SUCRA = 23.3%) and the Barthel Index (SUCRA = 71.1%). Combined acupuncture was ranked highest for the Alzheimer's Disease Assessment Scale-Activities of Daily Living (ADAS-ADL, SUCRA = 94.3%), although its effects did not reach statistical significance. Across analyses, heterogeneity was minimal (I[2] ≤ 4%), model convergence was stable, and no publication bias was detected. Overall, this BNMA suggests that combined or thermal acupuncture offers the strongest cognitive gains alongside AChEIs, whereas moderate-intensity aerobic exercise provides the most reliable functional support. Because overall functional improvements were modest and evidence for some interventions remains limited, the benefits appear selective rather than broad. Larger, standardized trials are needed to clarify these patterns and guide their use in practice.},
}

@article {pmid42179865,
year = {2026},
author = {Arp, AM and Bloom, GS and D'Abreu, A and Fansler, A and Meegan, K and Ratcliffe, S and Kapur, J and Manning, C},
title = {The use of memantine for prevention of Alzheimer's disease: Pilot feasibility study rationale and protocol.},
journal = {Contemporary clinical trials communications},
volume = {51},
number = {},
pages = {101644},
pmid = {42179865},
issn = {2451-8654},
abstract = {BACKGROUND: Alzheimer's disease (AD) affects over 6 million older adults in the Untiled States. Evidence suggests the neuropathology leading to the disorder begins decades earlier, calling for a preventative treatment that can be administered to at risk individuals. Memantine hydrochloride, an NMDA receptor antagonist, is a possible candidate for prophylactic treatment by diminishing excessive NMDA receptor activity.

METHODS: This is a 2-year, double-blind, randomized, placebo-controlled trial of memantine hydrochloride (1:1 randomization allocation using randomly permutated blocks of unequal size). Participants are APOε4 carriers slightly under the average age of AD symptom onset (50-65 years of age) with a positive family history of a first degree relative with AD. Amyloid PET scans are performed pre and post treatment. Cognitive assessments and physical and neurological examinations are completed at regular intervals throughout the feasibility trial.

DISCUSSION: This study will assess the feasibility of the use of memantine hydrochloride for prevention of AD. The primary aim is to determine feasibility of participants who a) enrolled among those found eligible, and b) completed the study among those randomized to a study arm. Exploratory aims include examination of cognitive and safety assessments. Although not powered to determine efficacy, the study will provide direction on design elements needed for a Phase III clinical trial. No formal hypotheses are included in this feasibility trial.

TRIAL REGISTRATION: Clinical Trials NCT05063851.},
}

@article {pmid42180238,
year = {2026},
author = {Wang, Y and Li, H and Zhou, J and Zhao, S and Yang, A and Li, Z},
title = {The clinical value of multimodal neuroimaging in monoclonal antibody therapy for Alzheimer's disease.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1761380},
pmid = {42180238},
issn = {1664-2295},
abstract = {Multimodal neuroimaging plays an indispensable role in the diagnosis, monitoring, and therapeutic evaluation of monoclonal antibody (mAb) therapies for Alzheimer's disease (AD). Structural MRI (sMRI) enables early detection of cerebral atrophy and amyloid-related imaging abnormalities (ARIA), a critical adverse effect associated with anti-Aβ immunotherapies. Positron emission tomography (PET) provides direct visualization and quantification of Aβ plaque clearance, serving as an objective biomarker of target engagement. Functional MRI (fMRI) has been investigated as a means to detect dynamic changes in brain network connectivity following treatment, though the evidence remains preliminary. The integration of these modalities significantly enhances diagnostic accuracy and allows for personalized assessment of treatment response. Furthermore, artificial intelligence (AI) technologies improve the efficiency and predictive power of imaging data analysis, supporting clinical decision-making. Despite these advances, challenges remain regarding the sensitivity and specificity of current imaging techniques, heterogeneity in treatment responses, and the need for long-term safety monitoring. Standardized imaging protocols, combined with multidisciplinary collaboration and robust AI-assisted modeling, are essential to optimize therapeutic outcomes and minimize risks in mAb-based AD treatment.},
}

@article {pmid42180249,
year = {2026},
author = {Miranda, DG and Carrouel, F and Attik, N and Araujo, GF and Lopes, NFDS and Marcucci, MC and Rodrigues, FP and Caires, GA and Vigerelli, H and Godoi, BH and Pacheco-Soares, C and Ramos, LP},
title = {Correction: Juglans regia and Pfaffia paniculata extracts: implications for periodontal disease treatment and correlation with Alzheimer's risk.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1850828},
doi = {10.3389/fcimb.2026.1850828},
pmid = {42180249},
issn = {2235-2988},
abstract = {[This corrects the article DOI: 10.3389/fcimb.2025.1585438.].},
}

@article {pmid42180526,
year = {2026},
author = {Zhang, X and Yu, X and Sha, L and Li, Y and Qiao, Q and Yu, X and Xu, Q},
title = {Reblastatin as a neuroprotective agent in temporal lobe epilepsy and excitotoxic conditions of Alzheimer's disease and Parkinson's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2964-2981},
pmid = {42180526},
issn = {2211-3835},
abstract = {Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors can reduce seizures in temporal lobe epilepsy (TLE) by upregulating excitatory amino acid transporter 2 (EAAT2, also known as GLT-1). While the Hsp90 inhibitor 17-AAG is effective, its long-term use raises toxicity concerns. This study aimed to identify a safer Hsp90 inhibitor by screening benzenoid ansamycin derivatives for higher binding affinity and lower toxicity. Among nine natural benzenoid ansamycins and their derivatives screened, reblastatin emerged as the top candidate, exhibiting the highest binding affinity to Hsp90. Compared to geldanamycin and 17-AAG, reblastatin demonstrated significantly lower cytotoxicity in HEK293 and HepG2 cells. Like 17-AAG, reblastatin upregulated EAAT2 levels by disrupting the association among Hsp90, EAAT2, and the 20S proteasome. In a kainic acid-induced TLE mouse model, reblastatin reduced seizure frequency by 50%, with long-term treatment showing toxicity comparable to vehicle controls. Additionally, behavioral tests revealed neuroprotective effects of reblastatin in mouse models of Alzheimer's disease and Parkinson's disease. These findings collectively suggest that reblastatin is a promising Hsp90 inhibitor for treating TLE and excitotoxic conditions associated with neurodegenerative diseases.},
}

@article {pmid42180530,
year = {2026},
author = {Zhao, W and Lai, Y and Li, Z and Yuan, Z and Wen, Z and Zhang, L},
title = {Targeting non-apoptotic regulated cell death (RCD) to treat neurodegenerative diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2601-2644},
pmid = {42180530},
issn = {2211-3835},
abstract = {Regulated cell death (RCD) is well-known as a controlled form of cell death regulated by one or more cascading signaling pathways. Over the past few decades, increasing evidence has implicated various non-apoptotic forms of RCD in neurons-including ferroptosis, parthanatos, necroptosis, pyroptosis, autophagic cell death, paraptosis, and cuproptosis-in the pathogenesis of neurodegenerative diseases (NDs) and their associated clinical manifestations. We provide an in-depth analysis of the associations between these RCDs and NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), and highlight the potential of modulating non-apoptotic RCD subtypes as neuroprotective targets. Besides, we highlight the crosstalk mechanisms among different non-apoptotic RCDs in NDs and the key targets regulating the crosstalk, which hold significant promise for developing dual-functional inhibitors that precisely modulate the pathological microenvironment and overcome drug resistance. As our understanding of death signaling networks deepens, such strategies may lead to breakthrough therapies for multiple NDs. Moreover, we further discuss the emerging small molecule compounds targeting non-apoptotic RCDs and their current research progress in clinical trials for the treatment of NDs, which may provide novel directions for related drugs. This comprehensive analysis paves the way for future research and therapeutic strategies aimed at harnessing non-apoptotic RCD pathways to mitigate neurodegeneration and improve patient outcomes.},
}

@article {pmid42180543,
year = {2026},
author = {Yang, Y and Liu, J and Liu, J and Wei, S and Kong, X and Mu, W and Liu, Y and Zhang, N},
title = {Advances in immune cell-based therapeutic agents for the treatment of inflammation-related diseases.},
journal = {Acta pharmaceutica Sinica. B},
volume = {16},
number = {5},
pages = {2794-2837},
pmid = {42180543},
issn = {2211-3835},
abstract = {Inflammation-related diseases account for over 50% of global disease-associated mortality; the core pathological mechanisms of these diseases are closely linked to functional dysregulation of immune cells such as macrophages and T cells. Aberrantly activated immune cells excessively secrete inflammatory mediators, which drive chronic inflammatory cascades and trigger irreversible tissue damage. In recent years, immune cell-based therapeutic agents (ICTAs) have garnered significant attention due to their inherent targeting specificity and immunomodulatory capabilities, encompassing whole immune cells, cell membranes, or extracellular vesicles serving as active therapeutics or delivery carriers. This review systematically elaborates on strategies for constructing ICTAs through nanoengineering, genetic engineering, and membrane-fused engineering, while outlining their integrating applications with other delivery devices. Furthermore, we summarize the preclinical and clinical trial advancements of ICTAs in various diseases such as tumors, rheumatoid arthritis, diabetes, atherosclerosis, Alzheimer's disease, inflammatory bowel disease, ischemia/reperfusion injury, sepsis, and hemophagocytic lymphohistiocytosis. These insights establish an interdisciplinary design framework for developing clinically applicable ICTAs and propose novel therapeutic approaches for inflammation-related diseases.},
}

@article {pmid41915038,
year = {2026},
author = {Xia, Y and Johnson, K and Fakhri, GE and Guehl, NJ and van de Giessen, E and Coomans, EC and Pijnenburg, YAL and Ossenkoppele, R and Groot, C},
title = {Bayesian modelling demonstrates clinically relevant heterogeneity in Tau PET patterns in Alzheimer's disease.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {53},
number = {7},
pages = {4664-4676},
pmid = {41915038},
issn = {1619-7089},
support = {10510022110010/ZONMW_/ZonMw/Netherlands ; WE.03-2024-06//Alzheimer Nederland/ ; 949570//H2020 European Research Council/ ; 10510022110010/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Traditionally, subgroups have been used to explore the effects of tau heterogeneity on cognition. However, categorization into rigid, exclusive subtypes, each with their own tau pattern, may overlook the fact that individual tau patterns are complex, and most individuals express features of multiple patterns. Mapping tau patterns in all their complexity has important clinical implications, as it may enable more accurate prognostication and support the development of personalized therapeutic strategies tailored to an individual’s unique tau profile.

METHODS: We applied a data-driven Bayesian model using Latent Dirichlet Allocation (LDA) to identify four covarying tau PET patterns in amyloid-positive individuals with symptomatic Alzheimer’s disease (AD) from the Amsterdam Dementia Cohort (ADC, N = 93, mean age = 65.3). The four latent tau spatial patterns identified via LDA were designated as follows: Limbic (Factor 1), characterized by predominant involvement of the limbic regions; Left TPC (Factor 2), centered on the left temporo-parietal cortex (TPC); Posterior (Factor 3), reflecting a posterior neocortical distribution; and MTL-sparing (Factor 4), showing relative sparing of limbic regions with diffuse neocortical tau deposition. Associations between individual loadings on each of these factors and cognitive domain scores were assessed using linear regression analyses. We then applied the ADC-derived model to an independent validation sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 162, mean age = 72.7) to extract individual factor loadings. Associations between factor loadings and contemporaneous cognitive performance were again tested using linear regression, and linear mixed-effects models were used to additionally explore associations with cognitive decline. All analyses were adjusted for age, sex, education, and clinical diagnosis.

RESULTS: In both the discovery and validation cohort, we identified distinct associations between tau factor loadings and cognitive performance. Higher loading on Factor 1: limbic tau was generally associated with relatively better baseline cognition and slower cognitive decline. Factor 2: left TPC tau was linked to worse baseline scores and faster decline in memory, MMSE and language scores but only in the ADNI cohort. Factor 3: posterior tau was associated with worse baseline MMSE in the ADC cohort and to worse visuospatial performance both cross-sectionally and longitudinally in the ADNI cohort. Factor 4: MTL-sparing tau was related to better longitudinal memory in the ADNI cohort.

CONCLUSION: This data-driven approach identified overlapping tau patterns that relate to distinct cognitive domains. The findings highlight the value of continuous factor modeling in understanding heterogeneity in Alzheimer’s disease. Such a refinement of quantifying tau heterogeneity may improve patient stratification, refine prognostic accuracy, and ultimately guide the development of individualized treatment strategies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-026-07868-5.},
}

@article {pmid42172309,
year = {2026},
author = {Unruh, D and Todtleben, J and Johnson, K and Schlichtmann, B and Szabo, M and Holland, M and Carlson, C and Hinson, J and Levin, S},
title = {Analytical and Clinical Validity of a High-Throughput, Fully Automated Immunoassay for Plasma Neurofilament Light Chain.},
journal = {The journal of applied laboratory medicine},
volume = {},
number = {},
pages = {},
doi = {10.1093/jalm/jfag052},
pmid = {42172309},
issn = {2576-9456},
abstract = {BACKGROUND: Neurofilament light chain (NfL) has emerged as a promising blood-based biomarker for neuroaxonal damage across neurological disorders. Clinical utility has been correlated with disease activity, treatment response, and prognosis. However, routine clinical laboratory implementation requires comprehensive analytical validation to ensure reliability and accuracy.

METHODS: A fully automated Access NfL research use only (RUO) immunoassay was evaluated on the DxI 9000 Immunoassay Analyzer from Beckman Coulter. Analytical validation in plasma assessed precision, analytical sensitivity, linearity, analytical specificity (interference), calibrator and sample stability, and method comparison to the Quanterix Simoa NfL assay. Clinical validity included comparisons of Alzheimer disease (Ad, N = 20) in plasma and multiple sclerosis (MS, N = 16) in serum, vs healthy controls (N = 20 and N = 23, respectively). Plasma-serum equivalence was validated.

RESULTS: The NfL assay met analytical criteria, with precision demonstrating coefficients of variation <3% across runs, a lower limit of quantification of 3.10 pg/mL, linearity with <12% deviation, and <10% interference. Plasma NfL samples remained stable for 18 h at room temperature (<7% difference) and refrigerated (<5%), and through 5 freeze-thaw cycles (<8%). Method comparison yielded high correlation (R2 = 0.981) with positive systematic proportional bias (Passing-Bablok slope = 3.02). Ad patients showed significantly elevated NfL levels (median 49.3 pg/mL, IQR: 28.9-67.8) vs controls (median 29.1 pg/mL, IQR: 22.6-33.8; P = 0.02). MS patients similarly demonstrated higher NfL (median 27.7 pg/mL, IQR: 22.5-50.6) vs controls (median 19.2 pg/mL, IQR: 15.1-25.6; P = 0.003).

CONCLUSIONS: The high-throughput Access NfL assay demonstrated analytical and clinical validity, supporting implementation in research and clinical laboratories.},
}

@article {pmid42172661,
year = {2026},
author = {Motisi Bertulli, A and Bezzio, C and Marsano, S and Corradini, I and Stranges, S and Matteoli, M and Armuzzi, A},
title = {Does inflammatory bowel disease play a role in cognitive decline? A systematic review.},
journal = {Journal of Crohn's & colitis},
volume = {20},
number = {5},
pages = {},
doi = {10.1093/ecco-jcc/jjag057},
pmid = {42172661},
issn = {1876-4479},
mesh = {Humans ; *Inflammatory Bowel Diseases/complications/psychology ; *Cognitive Dysfunction/etiology/epidemiology ; },
abstract = {BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has been increasingly linked to cognitive impairment (CI) and dementia, yet the underlying mechanisms driving this association remain poorly understood and population, clinical and experimental studies show controversial results. Among others, factors such as chronic inflammation, gut-brain axis dysfunction, and psychological comorbidities have been proposed as contributors to cognitive deficits in IBD patients. The objective of this systematic review was to evaluate the existing literature on the relationship between IBD and cognitive function, considering observational and preclinical studies, with the aim to identify key factors influencing CI and potential clinical implications. The main focus of this review is on the use of IBD treatments, which may have a potential impact on CI.

METHODS: We conducted a systematic review according to PRISMA guidelines. PubMed and Scopus were searched from database inception up to August 30, 2024, for studies assessing cognitive performance in individuals with IBD. Clinical and epidemiological studies, genetic investigations (Mendelian Randomization and Genome-wide Association studies), and preclinical models examining memory, attention, and executive functions were included. Two reviewers independently extracted data and assessed methodological quality and risk of bias.

RESULTS: The research yielded 66 included studies, including 31 populations studies, 13 genetics studies, and 22 preclinical research studies. Our findings suggest that patients with IBD may exhibit impaired cognitive function, particularly in memory, attention, and executive processing. Disease activity, chronic inflammation and psychological stress appear to contribute to these deficits, while some treatment strategies seem to mitigate the risk of CI.

CONCLUSION: IBD is associated with CI and increased dementia risk, with biologics potentially mitigating neuroinflammation-related decline. More longitudinal studies and randomized clinical trials, also on intermediate endpoints, are needed to clarify the neuroprotective role of some therapies and optimize treatment strategies.},
}

Humans
*Inflammatory Bowel Diseases/complications/psychology
*Cognitive Dysfunction/etiology/epidemiology

@article {pmid42172854,
year = {2026},
author = {Copeland, EN and Mohammad, A and Baranowski, BJ and Marcella, BM and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {95},
number = {},
pages = {127893},
doi = {10.1016/j.jtemb.2026.127893},
pmid = {42172854},
issn = {1878-3252},
abstract = {BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by a mutation to the dystrophin gene. Cognitive dysfunction is a lesser-known symptom of DMD; however, approximately one-third of patients experience it. Though the mechanisms underlying these dysfunctions are unknown, research points towards an Alzheimer's disease (AD)-like pathology in clinical and preclinical work. In a recent study, we previously demonstrated that inhibiting glycogen synthase kinase 3 (GSK3) through a combination of low-dose lithium supplementation and voluntary wheel running (VWR) improved muscle quality and function in the mdx mouse model of DMD. Interestingly, both VWR and GSK3 inhibition with lithium can exert neuroprotective effects against Alzheimer's pathology; however, whether this treatment can also benefit cognitive function in mdx mice remains unknown.

METHODS: Here, we conducted a brief follow-up study to determine whether inhibiting GSK3 with a combination of low-dose lithium supplementation and VWR would enhance novel object recognition in mdx mice, while also investigating potential mechanisms, including beta-secretase activity, Tau phosphorylation, and sarco(endo)plasmic reticulum calcium ATPase (SERCA) activity.

RESULTS: Our findings show that lithium and VWR treatment, on average, improved novel object recognition in mdx mice-a result that may be linked to enhanced SERCA activity within the hippocampus but not to any changes in beta-secretase activity or tau phosphorylation.

CONCLUSION: Taken together, these data point to the potential benefits of Li and VWR on cognitive function in mdx mice, highlighting the need for future research aimed at teasing out the potential mechanisms.},
}

@article {pmid42172936,
year = {2026},
author = {Li, Y and Li, H and Xu, Z and Zhou, SK and , },
title = {CLIS: Causality-inspired Longitudinal Image Synthesis and its application to Alzheimer's disease characterization.},
journal = {Medical image analysis},
volume = {112},
number = {},
pages = {104126},
doi = {10.1016/j.media.2026.104126},
pmid = {42172936},
issn = {1361-8423},
abstract = {Clinical decision-making relies heavily on causal reasoning and longitudinal analysis of clinical variables, which include demographic variables, biomarkers, measurements, etc., often stored in a tabular format, and visual medical images. For example, for a patient with Alzheimer's disease (AD), how might brain gray matter atrophy evolve over a year under a hypothetical change in the Aβ42 biomarker level in cerebrospinal fluid? Answering such hypothetical questions is important for diagnosis and follow-up treatment, yet these medical images are neither readily acquired nor effectively predicted by correlation-based image synthesis models. Hence, a Causality-inspired Longitudinal Image Synthesis (CLIS) model is valuable. Building such a CLIS model faces three primary challenges: mismatched dimensionality between high-dimensional images and low-dimensional tabular variables, inconsistent intervals in follow-up data, and the complexity of medical causal mechanisms. In this paper, we propose a CLIS model that addresses these challenges via a novel integration of generative imaging, continuous-time modeling, and structural causal models combined with a neural network. Specifically, we first depict dependencies among tabular variables - including demographics, clinical biomarkers, and brain volumes - using a tabular causal graph (TCG), and then extend this to a tabular-visual causal graph (TVCG) to synthesize brain MRIs in a causality-inspired manner. An independent variable is also introduced to explicitly model time intervals. We train our CLIS on the ADNI dataset and evaluate it on two additional AD datasets, demonstrating that the synthesized images are both high-quality and interpretable. Furthermore, the generated MRIs provide insights for AD characterization, illustrating the model's potential utility in clinical applications.},
}

@article {pmid42174650,
year = {2026},
author = {Dakhel, A and Vestin, J and Giedraitis, V and Nyholm, D and Ingelsson, M and Erlandsson, A},
title = {Characterization of a distinct form of vimentin in the neurodegenerative brain.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {42174650},
issn = {2051-5960},
mesh = {*Vimentin/metabolism ; Humans ; *Brain/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Parkinson Disease/metabolism/pathology ; Female ; Male ; Aged ; Astrocytes/metabolism ; Aged, 80 and over ; Middle Aged ; },
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.},
}

*Vimentin/metabolism
Humans
*Brain/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Parkinson Disease/metabolism/pathology
Female
Male
Aged
Astrocytes/metabolism
Aged, 80 and over
Middle Aged

@article {pmid42174734,
year = {2026},
author = {Xue, H and Bi, S and Wang, M and Zhu, X and Wang, F and Wang, Y and He, Y and Wang, Y and Liu, X and Cui, B and Li, N and Zhao, Z and Zhang, C and Wu, L and Qi, Z and Yan, S and Lu, J},
title = {Optimizing cutoffs for clinical interpretation of brain amyloid status using PET/MRI: a multisite study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02071-y},
pmid = {42174734},
issn = {1758-9193},
abstract = {BACKGROUND: Amyloid-β PET (Aβ-PET) imaging is playing an increasingly important role in the diagnosis and treatment of Alzheimer's Disease (AD). The Centiloid (CL) scale has been developed to standardize the measurements of Aβ PET imaging. Previous CL threshold settings were based on PET/CT, while our team's preliminary study found that CL values from PET/MRI are higher than those from PET/CT. Therefore, there is an urgent need to establish clinical interpretation cutoffs for Aβ status via PET/MRI to facilitate application in clinical practice.

METHODS: The clinical performance of Aβ PET/MRI and cerebrospinal fluid biomarkers were evaluated in a multisite cohort of 720 participants. Aβ-PET scans were visually read and quantified using CL method. A two-cutoff approach identified thresholds maintaining > 90% sensitivity/specificity and ≤ 20% intermediate cases, selected by maximal Youden index. Group comparisons of cerebrospinal fluid biomarkers and cognition used generalized linear models adjusted for age and sex.

RESULTS: The two-cutoff approach categorized Aβ-PET status as negative (CL ≤ 18.7), gray-zone (18.7-44.2), and positive (CL > 44.2). In Xuanwu cohort, it achieved an accuracy of 94.1%, a positive predictive value of 97.4%, a negative predictive value of 86.1%. In External cohort, the accuracy was 97.4%, positive predictive value 98.5%, negative predictive value 90.8%. Patients in the gray-zone group had lower cerebrospinal fluid(CSF) Aβ-42, Aβ-42/40 levels and a higher P-tau/Aβ-42 ratio.

CONCLUSIONS: This study established optimal CL-cutoff, providing a clinically applicable framework for interpreting Aβ PET/MRI findings. Incorporating a two-cutoff system facilitates the tracking of the AD continuum and supports individualized therapeutic decision-making.},
}

@article {pmid42175737,
year = {2026},
author = {Liang, S and Zhang, Q and Wang, X and Peng, L and Ji, X and Wang, J and Zhang, Y and Huang, J and Yang, J and Zhan, S and Xiao, Y and Liu, W and Chen, L},
title = {Electroacupuncture Improves the Learning and Memory by Modulating Hippocampal Glucose Metabolism through IGF1/IGF1R Signaling in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14241},
doi = {10.1002/advs.202514241},
pmid = {42175737},
issn = {2198-3844},
support = {82004440//National Natural Science Foundation of China/ ; 2024J09044//Fujian Provincial Natural Science Foundation of China/ ; 2025Y9600//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2024Y9533//Joint Funds for the innovation of science and Technology, Fujian Province/ ; 2023ZQNZD015//Health Service Research of Fujian Province/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and cerebral glucose hypometabolism. Emerging evidence suggests that modulating brain glucose metabolism represents a promising therapeutic strategy for AD. Here, we demonstrate that electroacupuncture (EA) improves cognitive function in 5×FAD mice by enhancing glucose metabolism in the hippocampus. EA treatment significantly attenuated learning and memory deficits and reduced β-amyloid (Aβ) deposition in 5×FAD mice. Further analysis revealed that these improvements were associated with enhanced hippocampal glucose metabolism and optimized information processing in the brain metabolic network. In addition, EA specifically activated the IGF1/IGF1R signaling pathway in the hippocampus, which promoted membrane translocation of GLUT3 and consequently enhanced neuronal glucose uptake. The glucose metabolic enhancement boosted tricarboxylic acid cycle activity and improved synaptic plasticity. Our findings establish a novel mechanism by which EA improves the learning and memory through the IGF1/IGF1R pathway, providing both theoretic and experimental support for the clinical application of EA in AD treatment.},
}

@article {pmid42175774,
year = {2026},
author = {Lin, Z and Jiang, Z and Chen, D and Liu, Y and He, Z and Ning, W and Wang, S and Guan, L},
title = {Novel Donepezil-Chalcone Hybrids as Potential Multifunctional Anti-Alzheimer's Disease Agents: Design, Synthesis, Computational Simulation, and In Vitro/In Vivo Biological Evaluation.},
journal = {Chemical biology & drug design},
volume = {107},
number = {5},
pages = {e70316},
doi = {10.1111/cbdd.70316},
pmid = {42175774},
issn = {1747-0285},
support = {22567024//The National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism/chemistry ; *Donepezil/chemistry/pharmacology/therapeutic use ; Molecular Docking Simulation ; Mice ; Humans ; *Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use ; Drug Design ; Peptide Fragments/metabolism ; Acetylcholinesterase/metabolism/chemistry ; *Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis ; Molecular Dynamics Simulation ; Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; Butyrylcholinesterase/metabolism/chemistry ; Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors ; *Chalcone/chemistry/pharmacology ; Male ; Protein Aggregates/drug effects ; },
abstract = {A novel series of donepezil-chalcone including pyridine, piperazine, phenylamide skeleton hybrids were designed, synthesized, and evaluated for their inhibitory activities against AChE and BChE. Subsequently, a subset of these derivatives was investigation to inhibit Aβ1-42 aggregation and promote Aβ1-42 disaggregation effects. Among them, compounds 8b, 8c, 8j, and 8ab possessing good activity were further assayed for their inhibitory effects on BACE-1 and GSK3β, as well as their PI displacement activity. 8b (AChE, IC50: 0.11 μM; BChE, IC50: 0.18 μM; Aβ1-42 aggregation, IC50: 3.40 μM; their ability to promote Aβ1-42 disaggregation, IC50: 4.53 μM; BACE-1, IC50: 1.82 μM; GSK3β, IC50: 0.98 μM) exhibited prominent bioactivities across the above assays. Meanwhile, the molecular docking and the molecular dynamics simulations were performed to analyze the interactions between 8b and the key amino acid residues of the target proteins, which verified the stability of the corresponding protein ligand complexes. Furthermore, 8b significantly attenuated the cytotoxicity induced by Fe[3+] and Cu[2+] in BV-2 microglial cells, L-Glu in HT-22 hippocampal neuronal cells, and Aβ1-42 in both BV-2 and SH-SY5Y neuroblastoma cells. Additionally, 8b reduced the levels of intracellular ROS and NO in LPS-stimulated BV-2 cells, demonstrating potent anti-inflammatory and neuroprotective properties. Acute toxicity tests in mice confirmed the safety profile of 8b. In in vivo studies, compound 8b effectively protected against neuroinflammation 8b ameliorated cognitive deficits in mice induced by AlCl3 combined with L-galactose, which was associated with the upregulation of p-GSK3β and the downregulation of p-Tau expression. In conclusion, 8b holds great potential as a promising multitarget-directed new lead compound for the treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism/chemistry
*Donepezil/chemistry/pharmacology/therapeutic use
Molecular Docking Simulation
Mice
Humans
*Cholinesterase Inhibitors/chemistry/pharmacology/therapeutic use
Drug Design
Peptide Fragments/metabolism
Acetylcholinesterase/metabolism/chemistry
*Neuroprotective Agents/chemistry/pharmacology/therapeutic use/chemical synthesis
Molecular Dynamics Simulation
Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
Butyrylcholinesterase/metabolism/chemistry
Amyloid Precursor Protein Secretases/metabolism/antagonists & inhibitors
*Chalcone/chemistry/pharmacology
Male
Protein Aggregates/drug effects

@article {pmid42176081,
year = {2026},
author = {Ibrahim, RW and AlSheikh, MH},
title = {Model Validation Pipeline Against Longitudinal Alzheimer's Biomarker Data.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {42176081},
issn = {1559-0089},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; Biomarkers/metabolism ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; *Brain/metabolism ; *Models, Neurological ; Longitudinal Studies ; Connectome/methods ; Computer Simulation ; },
abstract = {This study develops a fractional-order model of Alzheimer's disease using a [Formula: see text]-generalized Atangana-Baleanu-Caputo (ABC) operator to capture the spatiotemporal dynamics of amyloid-beta and tau protein spread, coupled with a neuron regeneration mechanism. The fractional parameters α, [Formula: see text], and τ control memory depth, deformation of the kernel, and temporal scaling, respectively. Numerical simulations demonstrate that: (i) intermediate fractional orders [Formula: see text] produce biologically realistic propagation delays, (ii) lower [Formula: see text] values enhance nonlocal interactions and accelerate tau diffusion across the connectome, and (iii) increasing the scaling parameter τ slows accumulation, mimicking effective clearance or treatment response. Incorporating a treatment term with drug diffusion and decay reveals that sustained low decay rates ([Formula: see text]) markedly reduce tau concentrations and protect neuron populations. These findings show that the [Formula: see text]-ABC framework not only captures the hereditary and memory effects of Alzheimer's progression but also provides a flexible platform for simulating therapeutic interventions and predicting disease trajectories using real brain connectome data.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Humans
Biomarkers/metabolism
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
*Brain/metabolism
*Models, Neurological
Longitudinal Studies
Connectome/methods
Computer Simulation

@article {pmid42176392,
year = {2026},
author = {Baron, KG and Alcántara, C and López, I and Euler, M and Baucom, BRW and Bermudez, B and Arones, Y and Carbajal-Salisbury, S and Fabian, G and Grandner, M and Gorovoy, S and Lopez, S and Parthasarathy, S and Troxel, W},
title = {Protocol for Nuestro Sueño: A randomized trial of a couples-based intervention to improve PAP adherence and sleep health among Hispanic patients beginning positive airway pressure (PAP) and their partners.},
journal = {Sleep medicine},
volume = {145},
number = {},
pages = {109019},
doi = {10.1016/j.sleep.2026.109019},
pmid = {42176392},
issn = {1878-5506},
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) is more common among Hispanic individuals and contributes to risk for cardiometabolic diseases, dementia and poor quality of life. Positive airway pressure (PAP) improves sleep and quality of life, and culturally adapted interventions are promising for increasing treatment engagement. The goal of this study is to test Nuestro Sueño, a culturally adapted couples-based intervention to promote positive airway pressure adherence and sleep health for Hispanic couples in which one partner is recently diagnosed with OSA.

METHODS: We are conducting a two-arm, parallel group, single blind, randomized controlled pilot/feasibility trial to compare our novel culturally adapted treatment to an information control (IC). Nuestro Sueño is a culturally adapted dyadic behavioral intervention based on a transdiagnostic model. The digital health program involves 3- weekly sessions delivered via telehealth with a community health worker. Content is focused on education about OSA and PAP, improving both partner's sleep quality, increasing partner support and communication, and couple-level goal-setting around sleep and PAP use. The IC includes standardized patient educational materials. Both groups receive the usual follow-up care. Assessments will be completed pre-treatment, 1 and 3 months after starting PAP. Our main outcomes are feasibility and treatment satisfaction. Secondary outcomes include comparing Nuestro Sueño to IC for PAP adherence, sleep quality (self-report and objective) and cognitive measures of memory, processing speed and verbal fluency.

DISCUSSION: Nuestro Sueño is a novel culturally adapted intervention focused on improving PAP adherence and sleep health among couples in which one partner is recently diagnosed with OSA. Results of this study will be used to inform the design of a subsequent fully adequately-powered clinical trial. If successful, this intervention could significantly advance current clinical practice in the treatment of OSA and sleep health more comprehensively as well as promote sleep health equity among Hispanic patients, who are more likely to face challenges to obtaining diagnosis and treatment for OSA.

TRIAL REGISTRATION: Clinicaltrials.gov, NCT06649929.},
}

@article {pmid42168776,
year = {2026},
author = {van Dyck, CH},
title = {Letter to the editor response for: "Schneider LS, Kennedy RE, Cutter G. Caution in interpreting disease-modification claims with lecanemab: selective reporting and causal inference. Alzheimer's & Dementia. 2026".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71485},
doi = {10.1002/alz.71485},
pmid = {42168776},
issn = {1552-5279},
}

@article {pmid42170124,
year = {2026},
author = {Patel, D and Patel, T and Patel, PN},
title = {Integrative Analysis of Pharmacological and Non-pharmacological Interventions in Alzheimer's Dementia.},
journal = {Cureus},
volume = {18},
number = {4},
pages = {e107386},
pmid = {42170124},
issn = {2168-8184},
abstract = {Alzheimer's dementia is a progressive neurodegenerative disorder in which cognitive decline, neuropsychiatric symptoms, and functional dependence emerge from a long preclinical and prodromal phase. Effective care increasingly requires an integrative approach: (1) disease-modifying pharmacology for selected patients early in the symptomatic course, (2) symptomatic pharmacotherapy for cognition and behavioral symptoms when benefits outweigh harms, and (3) non-pharmacological interventions that meaningfully affect quality of life, caregiver burden, safety, and functional outcomes across all stages. Recent advances, particularly anti-amyloid monoclonal antibodies, have reshaped early Alzheimer's treatment while raising new implementation challenges around biomarker confirmation, monitoring for amyloid-related imaging abnormalities (ARIA), and health-system capacity. Evidence also supports structured non-pharmacological strategies (e.g., cognitive stimulation, physical activity, caregiver programs, and environmental and behavioral approaches for agitation) as core therapies rather than "adjuncts." This narrative review synthesizes the evidence base and offers a practical, stage-based framework for combining pharmacological and non-pharmacological therapies, emphasizing person-centered goals, safety, feasibility, and equity.},
}

@article {pmid42171909,
year = {2026},
author = {Hammad, MO and Shady, T and Moanes, B and El-Sharkawy, AR and Galal, AM and Tawfeek, AE and El-Sisi, AEM and Sameh, A and Mahrous, S and Atya, N and Essam, A and El-Desouky, S and Abd El-Aziz, MH},
title = {Quinoa seed (Chenopodium quinoa W.) extract attenuates Alzheimer's disease-like neurodegeneration: Targeting the SLC7A11/GPX4 pathway.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171909},
issn = {1573-4978},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; *Chenopodium quinoa/chemistry/metabolism ; Rats ; Male ; *Plant Extracts/pharmacology ; Disease Models, Animal ; Oxidative Stress/drug effects ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Seeds/chemistry ; Hippocampus/metabolism/drug effects/pathology ; Antioxidants/pharmacology/metabolism ; Aluminum Chloride ; Signal Transduction/drug effects ; Cognitive Dysfunction ; Maze Learning/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and hippocampal neuronal loss. Targeting ferroptosis-related pathways represents a promising therapeutic strategy.

OBJECTIVE: This study aimed to investigate the potential effect of quinoa (Chenopodium Quinoa W.) seed extract in an aluminum chloride (AlCl₃)-induced rat model of AD, with a particular focus on the SLC7A11/GPX4 antioxidant axis and NCOA4-mediated ferritinophagy.

METHODS: Adult male rats were randomly divided into four groups (n = 6): GI (Control), GII (AD), GIII (Quinoa + AD), and GIV (Alzemenda + AD). AD was induced by oral AlCl₃ administration. Quinoa extract and Alzemenda were administered concurrently with AlCl₃ throughout the experimental period. Behavioral performance was evaluated using the Morris Water Maze and Open Field Test. Oxidative stress markers, iron parameters, gene expression, and histopathological changes in the hippocampus were assessed.

RESULTS: GII exhibited significant cognitive impairment, increased lipid peroxidation, depletion of antioxidant defenses, downregulation of SLC7A11, and marked hippocampal iron deposition compared with GI. Treatment with quinoa (GIII) significantly improved learning and memory, restored GPX4 activity and GSH levels, upregulated SLC7A11 expression, and attenuated hippocampal iron deposition. GIV showed comparable behavioral and histological improvement. Systemic iron indices, as well as hippocampal FPN1 and NCOA4 expression, did not differ significantly among groups.

CONCLUSION: Quinoa seed extract exerts ameliorating effects in AlCl₃-induced AD by suppressing oxidative stress-associated neurodegeneration through preservation of the SLC7A11/GSH/GPX4 axis rather than modulation of iron export or ferritinophagy pathways.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/chemically induced
*Chenopodium quinoa/chemistry/metabolism
Rats
Male
*Plant Extracts/pharmacology
Disease Models, Animal
Oxidative Stress/drug effects
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
Seeds/chemistry
Hippocampus/metabolism/drug effects/pathology
Antioxidants/pharmacology/metabolism
Aluminum Chloride
Signal Transduction/drug effects
Cognitive Dysfunction
Maze Learning/drug effects

@article {pmid42171931,
year = {2026},
author = {Shukla, S and Singh, RK},
title = {Crosstalk between death-associated protein kinase 1-regulated mechanisms and dysfunctions in alzheimer's disease.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42171931},
issn = {1573-4978},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Death-Associated Protein Kinases/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; Neurons/metabolism/pathology ; Animals ; Signal Transduction ; Cell Death ; Reactive Oxygen Species/metabolism ; tau Proteins/metabolism ; Brain/metabolism ; Autophagy ; },
abstract = {Alzheimer's disease (AD) is a chronic progressive neurocognitive disorder manifested by increased production and deposition of amyloid beta (Aβ), abnormal tau phosphorylation, and formation of neurofibrillary tangles (NFTs). In addition, the disease progression is found to be associated with neuronal cell death, elevated levels of reactive oxygen species, mitochondrial dysfunction, and loss of synaptic plasticity in specific regions of the brain. AD is seventh leading cause of death and over more than 70%-80% of 57 million people having dementia develop AD worldwide. The disease population is also severely increasing at an alarming rate globally. The currently available treatment strategies remain insufficient to cure the disease because AD involves very complex pathways during its progression. Death-associated protein kinase 1 (DAPK1) is identified as a promising next-generation therapeutic drug target for the management of AD. It belongs to a family of serine/threonine kinases that influences different hypotheses involved in AD pathogenesis, such as tauopathies, Aβ hypothesis, redox, and autophagy pathways. In this review, we highlight the involvement of DAPK1 in various molecular pathways associated with AD pathogenesis and the crosstalk between DAPK1 and synaptic dysfunction and neuronal cell death implicated in AD. Moreover, the various small molecules, microRNAs, and phytoconstituents have been discussed, which have the potential to be developed as a treatment strategy targeting DAPK1-related pathological pathways in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Death-Associated Protein Kinases/metabolism/genetics
Amyloid beta-Peptides/metabolism
Neurons/metabolism/pathology
Animals
Signal Transduction
Cell Death
Reactive Oxygen Species/metabolism
tau Proteins/metabolism
Brain/metabolism
Autophagy

@article {pmid42172039,
year = {2026},
author = {Han, X and Xue, J and Zhang, Q and Li, R and Guo, X and Duan, Q and Sang, S},
title = {Nitric oxide-enhanced blood-brain barrier penetration and mitochondria-targeted antioxidant carbon dots for Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00133e},
pmid = {42172039},
issn = {2050-7518},
abstract = {Alzheimer's disease (AD) involves a complex pathogenesis in which the β-amyloid (Aβ) cascade and oxidative stress hypotheses interact through mitochondrial dysfunction, forming a vicious cycle that underscores the need for multi-targeted therapeutic strategies. In this study, multifunctional carbon dots (EMA-CDs) were rationally designed and synthesised via a simple one-pot hydrothermal approach to integrate antioxidant activity, nitric oxide (NO) release capability, and mitochondrial targeting. EMA-CDs exhibited potent reactive oxygen species (ROS) scavenging abilities, efficiently eliminating hydroxyl radicals, superoxide anions, and DPPH radicals with rates exceeding 80%. Their mitochondrial specificity further alleviated intracellular oxidative stress and neuroinflammation. Notably, EMA-CDs at low concentrations (80 µg mL[-1]) markedly inhibited Aβ42 aggregation and promoted fibril disassembly, achieving inhibition and depolymerisation efficiencies of approximately 97.1% and 99.4%, respectively. In addition, EMA-CDs promoted NO production, which in turn modulated the expression of MMP-9 and ZO-1 proteins. This led to a reversible and transient opening of the blood-brain barrier (BBB), resulting in an enhanced penetration efficiency with a cumulative rate of 65.4% over 12 h. Furthermore, in the C. elegans CL2006 model, EMA-CDs significantly alleviated Aβ42 plaque deposition and reduced intracellular ROS levels by approximately 55%. Moreover, EMA-CDs extended the mean lifespan of the worms by about 6 days and enhanced reproductive capacity to 1.25-fold of the control, demonstrating potent in vivo neuroprotective and antioxidative stress effects. Collectively, this study demonstrates that EMA-CDs function as a versatile therapeutic platform for AD treatment and provide a promising avenue for the development of multi-target nanotherapeutics and novel AD intervention strategies.},
}

@article {pmid41965633,
year = {2026},
author = {Mansel, CO and Ghisays, V and Mahnken, JD and Swerdlow, RH and Reiman, EM and Karnes, JH and Denny, JC and Veatch, OJ},
title = {Downward bias in the association between APOE and Alzheimer's disease using prevalent and by-proxy disease sampling in the All of Us research program.},
journal = {BMC medical genomics},
volume = {19},
number = {1},
pages = {},
pmid = {41965633},
issn = {1755-8794},
support = {R01 HL156993/HL/NHLBI NIH HHS/United States ; OT2 OD026549/OD/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; R01 HL158686/HL/NHLBI NIH HHS/United States ; OT2 OD036485/OD/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; R21 HL172036/HL/NHLBI NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; P30 AG072973/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; 1OT2OD026549/NH/NIH HHS/United States ; ZIA HG200417/NH/NIH HHS/United States ; P30 AG035982/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Recent genome-wide association studies for Alzheimer’s Disease and related dementias (ADRD) have increased statistical power via larger analysis datasets from biobanks by (1) including non-age-matched controls and prevalent cases, and/or (2) including individuals who report a family history of ADRD as proxy cases. However, these methods have the potential to increase noise and distort genetic associations which are important for genomic-informed prevention and treatment of ADRD. Here, we sought to understand how the effect sizes of genetic associations in ADRD could be sensitive to these methodological choices, using APOE genotypes as an example.

METHODS: Participants in the All of Us Research Program over the age of 49 at enrollment (n = 229,722) were assigned one of four categories: incident ADRD (developed after enrollment in All of Us), prevalent ADRD (present on enrollment), proxy ADRD (participant noted a family history of ADRD), and control (no history or diagnosis of ADRD). ADRD diagnoses were determined using available electronic health records and APOE genotype was determined using whole-genome sequencing. Effect sizes for the associations between APOE risk alleles and ADRD diagnoses were compared using polychotomous logistic regression and presented as adjusted generalized ratios (AGR).

RESULTS: The mean age of the cohort was 64 ± 9 years, and it was 57% female; 65% clustered predominantly with European genetic reference populations. Among the participants, 733 (0.3%) had prevalent ADRD, 684 (0.3%) had incident ADRD, and 19,186 (8.4%) reported a family history of ADRD (proxy ADRD). The effect size for APOE ε4 heterozygote was similar for proxy ADRD (AGR [95% CI]: 2.10 [1.96–2.24]) but attenuated for prevalent ADRD (1.38 [1.17–1.63]) compared to incident ADRD (2.13 [1.81–2.50]). For APOE ε4 homozygotes, the effect sizes were significantly attenuated in both proxy (3.53 [2.93–4.26]) and prevalent (3.12 [2.20–4.45]) ADRD. Furthermore, APOE and ADRD association effect sizes increased when restricting the control (no ADRD) group to older age brackets.

CONCLUSIONS: Our study highlights how genetic associations with ADRD can be sensitive to how cases are defined in biobanks like All of Us, with effect sizes downwardly biased when using prevalent or by-proxy cases compared to incident cases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12920-026-02362-1.},
}

@article {pmid42164617,
year = {2026},
author = {Garnier-Crussard, A and Dadar, M and Villain, N and Charidimou, A and Boulouis, G and Cotton, F and Brickman, AM and Chételat, G},
title = {White matter hyperintensities in Alzheimer's disease in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70349},
pmid = {42164617},
issn = {2352-8729},
abstract = {White matter hyperintensities (WMHs) are highly prevalent in Alzheimer's disease (AD) and arise from interacting vascular pathologies (including hypertensive small vessel disease and cerebral amyloid angiopathy) alongside inflammatory and neurodegenerative processes. In the era of anti-amyloid monoclonal antibodies, this heterogeneity is increasingly relevant for both treatment efficacy and safety. WMHs may signal mixed AD-vascular pathology that dilutes the cognitive benefit of amyloid-targeting therapies and may also index vulnerability of the neurovascular unit that predisposes to amyloid-related imaging abnormalities (ARIAs), although direct evidence remains limited. In this perspective, we synthesize current knowledge on the origins of WMHs in AD, review advanced magnetic resonance imaging and biomarker approaches that aim to refine lesion characterization in vivo, and discuss how WMHs should be interpreted in memory clinic practice when considering anti-amyloid therapies. We conclude with a research roadmap to integrate WMH phenotyping into precision risk-benefit assessment and ARIA prediction .},
}

@article {pmid42164658,
year = {2026},
author = {Liu, X and Jia, L and Wu, K and Chen, M and Sun, J and Yang, C and Xu, C and Sun, J and Wang, J and Dai, L},
title = {Exploring and Targeting the Connection of Iron and Copper Homeostasis to Neurodegenerative Diseases.},
journal = {MedComm},
volume = {7},
number = {},
pages = {e70766},
pmid = {42164658},
issn = {2688-2663},
abstract = {Iron (Fe) and copper (Cu) are vital micronutrients that regulate many critical physiological processes in the human body, with their homeostasis in the central nervous system (CNS) being essential for proper neuronal function. Disruptions in their metabolism and regulatory pathways have been associated with the pathogenesis of various forms of neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). Despite growing research on metal homeostasis, the intricate molecular mechanisms that link iron and copper metabolism to the initiation and progression of NDDs remain insufficiently elucidated. In this review, we provide a systematic overview of the metabolic processes of iron and copper in the body and CNS, highlighting their interactions with many metal-binding proteins, including transporters, storage proteins, and important intrinsically disordered proteins (e.g., amyloid β-protein, tau, and alpha-synuclein) involved in NDDs. We further dissect the downstream effects of metal ion dyshomeostasis on cellular redox balance, neuroinflammation, autophagy, organelle interaction network, and cell death. Additionally, we discuss current therapeutic strategies aimed at targeting iron and copper dyshomeostasis, as well as the emerging role of artificial intelligence in this field of research. By integrating metal metabolism, metal-protein interactions, the effect of metal dyshomeostasis on downstream biological processes, and potential intervention strategies, this review serves as a comprehensive reference for understanding the pathogenesis of NDDs and offers new perspectives for developing effective therapeutics. Overall, this review underscores the significance of reinstating metal balance for the treatment of neurodegeneration.},
}

@article {pmid42166005,
year = {2026},
author = {Kariminejad-Farsangi, H and Kariminejad-Farsangi, H and Mir, Y and Sheibani, V and Joushi, S},
title = {Mechanistic insights into mesenchymal stem cell therapy for cognitive impairments in Alzheimer's disease models: a systematic review and meta-analysis.},
journal = {Molecular and cellular biochemistry},
volume = {},
number = {},
pages = {},
pmid = {42166005},
issn = {1573-4919},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatment options that primarily offer symptomatic relief. Mesenchymal stem cells (MSCs) have shown promise in preclinical studies due to their neuroprotective, immunomodulatory, and regenerative properties. This systematic review and meta-analysis aimed to assess the effects of MSC therapy on cognitive performance and molecular pathology in animal models of AD.A systematic search was conducted in PubMed, Web of Science, Scopus, Embase, ProQuest, and gray literature sources. This study included in vivo interventional animal studies that evaluated the effects of MSCs on cognitive outcomes in Alzheimer's disease models using the Morris Water Maze test. The standardized mean difference (SMD) was used as the effect size, and data were synthesized using a random-effects model. Study quality was assessed using the SYRCLE risk of bias tool. Publication bias was evaluated through funnel plots, Egger's test, and the trim-and-fill method. Sensitivity analysis was performed using the leave-one-out method and further supported by a risk-of-bias-based approach.A total of 51 studies met the inclusion criteria, of which 37 were included in the meta-analysis. The findings indicated that MSC therapy significantly reduced escape latency (SMD = -1.18, 95% CI -1.46 to-0.89, I[2] = 56.81%, P = 0.00) and increased time spent in the target quadrant (SMD = 1.93, 95% CI 1.46 to 2.40, I[2] = 78.63%, P = 0.00). MSC treatment also led to an increase in hippocampal BDNF levels and a reduction in Aβ deposition and pro-inflammatory cytokines such as IL-1β and TNF-α. However, the effect on IL-6 levels was not statistically significant.MSCs Improve cognitive function and modulate pathological features in AD animal models. Further high-quality studies with standardized protocols and broader literature inclusion are needed to support clinical translation.},
}

@article {pmid42166031,
year = {2026},
author = {Xu, X and Ni, Z and Wang, YB and Fan, SS and Du, Y and Wang, X and Meng, XY},
title = {Decoding shared pathogenic networks of oxidative stress in neuropsychiatric disorders to prioritize multi-target therapeutics from natural products.},
journal = {Cell biology and toxicology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10565-026-10208-w},
pmid = {42166031},
issn = {1573-6822},
support = {2508085QC099//Natural Science Foundation of Anhui Province of China/ ; 2025AHGXZK40182//Natural Science Research Project for Youth of Higher Education Institutions of Anhui Province/ ; },
abstract = {BACKGROUND: Neurodegenerative and psychiatric disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and schizophrenia (SZ), are characterized by progressive neuronal loss and synaptic dysfunction. Despite their severity, effective disease-modifying treatments remain unavailable, largely due to the elusive nature of their underlying molecular mechanisms.

METHODS: To elucidate these mechanisms, we conducted an integrative systems biology analysis incorporating transcriptomic datasets, in silico proteomic networks, and inferred metabolomic profiles. Machine learning (ML) and deep learning (DL) models were employed to identify regulatory networks associated with oxidative stress, immune response, and synaptic signaling. Furthermore, network pharmacology approaches were applied to explore multi-target intervention strategies using bioactive compounds from traditional Chinese medicine (TCM).

RESULTS: Our integrative analysis revealed extensive overlap in dysregulated biological processes across all four disorders, particularly involving oxidative stress and immune activation. We identified TP53, NFE2L2, and PPP3CA as central regulatory hubs driving these pathologies. Notably, computational predictions highlighted that TCM-derived compounds, specifically stigmasterol and dodecanoic acid, exhibit promising multi-target effects for modulating these oxidative and inflammatory responses. Subsequent in vivo experimental validation was performed exclusively to corroborate the disease-associated pathways and core gene dysregulation in an Aβ42-induced AD model. These findings demonstrated molecular and behavioral phenotypes consistent with our multi-dimensional computational predictions, establishing a robust mechanistic rationale that merits future in vivo pharmacological validation for the predicted bioactive compounds.

CONCLUSION: This study highlights the utility of a multi-disease, multi-dimensional framework in uncovering shared pathogenic signatures. By integrating computational analytics with pharmacological modeling and experimental validation, we identified key regulatory genes and natural compounds with therapeutic potential. These findings provide a theoretical foundation for the development of multi-target, personalized treatment strategies against neurodegeneration.},
}

@article {pmid42166820,
year = {2026},
author = {Czarnota-Łydka, K and Kucwaj-Brysz, K and Cios, A and Mordyl, B and Głuch-Lutwin, M and Jastrzębska-Więsek, M and Partyka, A and Honkisz-Orzechowska, E and Karcz, T and Pakulska, J and Satała, G and Żesławska, E and Dąbrowska, M and Starek, M and Więcek, M and Kurowska, K and Pyka, P and Brunetti, L and Leuci, R and Piemontese, L and Nitek, W and Wesołowska, A and Carrieri, A and Handzlik, J},
title = {New chalcogen-optimized 1,3,5-triazines as dual 5-HT6R/FAAH modulators: A versatile approach to neurodegenerative disorders.},
journal = {European journal of medicinal chemistry},
volume = {315},
number = {},
pages = {118966},
doi = {10.1016/j.ejmech.2026.118966},
pmid = {42166820},
issn = {1768-3254},
abstract = {The clinical failure of selective serotonin 5-HT6 receptor (5-HT6R) antagonists in Alzheimer's disease (AD) highlights the need for multitarget therapeutic strategies addressing the multifactorial nature of neurodegeneration. Building upon our pioneering discovery of the first-in-class dual 5-HT6R/FAAH (fatty acid amide hydrolase) modulators among O-ether triazine compounds, we here report a comprehensive lead-optimization campaign centered on the triazine-based compound MR3b, identified as a promising lead in the search for AD treatment. Structural modifications based on scaffold contraction and chalcogen bioisosterism generated a focused library of 1,3,5-triazine derivatives with diversified GPCR and FAAH profiles. Several compounds displayed nanomolar affinities for 5-HT6R, 5-HT2AR, and D2R, alongside improved FAAH inhibition and antioxidant properties. Sulfur and selenium substitutions markedly enhanced receptor affinity and reduced cytotoxicity compared to the oxygen-containing lead. Selected compounds demonstrated significant neuroprotective effects in cellular models of AD-related pathology, including mitochondrial dysfunction, amyloid-β, and glutamate-induced toxicity. Furthermore, the thio-analogue 4c effectively reversed memory deficits in vivo, showing superior CNS penetration (Kp,brain = 0.78), an expanded therapeutic window (NOR test), and improved safety relative to MR3b. This study identified compound 4c as a second-generation lead and underscores the potential of multitarget triazine-based ligands combining serotonergic modulation and FAAH inhibition as potential disease-modifying candidates for AD and related neurodegenerative disorders.},
}

@article {pmid42167685,
year = {2026},
author = {Lee, YW and Cho, YE and Kim, SY and Cho, SY and Lee, SJ and Do, YJ and Lee, NH and Kim, DH and Ryu, JH and Bae, HJ and Park, SJ},
title = {Paeonol ameliorates scopolamine- and β-amyloid 1-42 oligomer-induced cognitive impairments through modulation of the TGR5-PKA-cAMP response element-binding-brain-derived neurotrophic factor pathway and inhibition of acetylcholinesterase.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106188},
doi = {10.1016/j.neuint.2026.106188},
pmid = {42167685},
issn = {1872-9754},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and cholinergic signaling deficits. Paeonol (2-hydroxy-4-methoxyacetophenone), a phenolic compound derived from Paeonia suffruticosa, has well-documented neuroprotective activity, but potential cognitive benefits and the underlying mechanisms have not been widely examined. Here, we investigated the potential of paeonol to improve cognitive function in scopolamine- and Aβ1-42 oligomer-induced mouse models of AD. Paeonol significantly improved the performance of both models in the Y-maze, novel object recognition, and passive avoidance tests, particularly at 10 mg/kg. Western blotting of excised brain tissue revealed that paeonol treatment reversed scopolamine- and Aβ1-42 oligomer-induced suppression of hippocampal PKA and cAMP response element-binding (CREB) phosphorylation and concomitantly enhanced brain-derived neurotrophic factor (BDNF) expression. Notably, paeonol also reversed scopolamine- and Aβ1-42-induced downregulation of Takeda G-protein-coupled receptor 5 (TGR5), an upstream regulator of the PKA-CREB-BDNF pathway, and molecular docking simulations predicted a possible paeonol-TGR5 interaction. Moreover, paeonol suppressed scopolamine-induced elevation of acetylcholinesterase activity with efficacy comparable to the clinical inhibitor donepezil. These findings support the potential of paeonol as a naturally sourced multitarget therapeutic agent for AD.},
}

@article {pmid41965687,
year = {2026},
author = {Hamed, FM and Mady, MS and Elgayed, SH and Mansour, YE and Mahgoub, S and Lai, KH and Lin, CY and Elsayed, HE and Moharram, FA},
title = {Carpoxylon macrospermum leaf extract and its phenolic compounds: a multi-targeted therapeutic remedy for Alzheimer's disease.},
journal = {BMC complementary medicine and therapies},
volume = {26},
number = {1},
pages = {},
pmid = {41965687},
issn = {2662-7671},
support = {MOST 111-2320-B-038-040-MY3, 113-2628-B-038-009-MY3, and 113-2321-B-255-001//National Science and Technology Council of Taiwan/ ; },
abstract = {BACKGROUND: Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder with a significant impact, especially on elderly people. Although no current treatment is available for AD, several studies have been conducted to discover alternative remedies capable of managing its symptoms and slowing the progression. Accordingly, herein we analysed the phenolic composition and investigated the defatted aqueous methanol extract (DAE) of Carpoxylon macrospermum H.Wendl. & Drude (Family Arecaceae) leaves against key enzymes in addition to oxidative and inflammatory markers involved in AD progression.

METHODS: NMR and mass spectrometry elucidated the phenolic compounds. Human carbonic anhydrase (hCA), human acetyl cholinesterase (AChE), and cyclo-oxygenase 2 (COX-2) inhibitor screening kits were used to assess the enzyme-inhibitory potential. Lipo-poly saccharide (LPS)-induced murine macrophage (RAW 264.7) in vitro model was used to test the anti-inflammatory effect. Molecular docking studies were conducted using AutoDock Vina.

RESULTS: Chlorogenic acid (1), rutin (2), hesperidin (3), vanillic acid (4), and p-hydroxybenzoic acid (5) have been isolated. The DAE and compounds 2 and 4 significantly inhibited hCA enzyme with IC50 equivalent to 0.160 ± 0.008, 0.243 ± 0.012, and 0.290 ± 0.015 µg/mL, and AChE enzyme with an IC50 corresponding to 3.732 ± 0.13, 0.868 ± 0.03, and 0.597 ± 0.02 µg/mL, respectively. Additionally, they demonstrated potent anti-inflammatory activity by inhibiting the COX-2 enzyme with IC50 values of 4.602 ± 0.17, 2.806 ± 0.10, and 0.849 ± 0.03 µg/mL, respectively. The DAE, 2 and 4 reduced IL-2 to 3.49 ± 0.12—7.018 ± 0.24 pg/mL; IL-4 to 6.019 ± 0.21–12.07 ± 0.41 pg/mL, and TNF-α to 323.65 ± 11.10–501.88 ± 17.21 pg/mL, respectively. Western blotting revealed a decrease in iNOS protein expression. Rutin showed improved docking scores (-8.92 and -7.92 kcal/mol) with AChE and hCA, while 100 ns Molecular Dynamc Simulations (MDS) showed that rutin maintained stable interactions with the proteins throughout the simulations.

CONCLUSION: C. macrospermum extract and its phenolics are promising candidates for AD management, though additional in vivo and clinical studies are needed.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-026-05365-8.},
}

@article {pmid42158158,
year = {2026},
author = {Pozuelo Moyano, B and Orgeta, V and von Gunten, A and Vandel, P and Ma, R and Stewart, R and Mueller, C},
title = {Late-life difficult-to-treat depression and dementia subtypes: a naturalistic cohort study using electronic health records.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1795874},
pmid = {42158158},
issn = {1664-0640},
abstract = {INTRODUCTION: Late-life difficult-to-treat depression (LL-DTD) and dementia frequently coexist in later life, but it remains unclear whether clinical and sociodemographic characteristics, as well as medication exposure patterns, differ across dementia subtypes among older adults with both conditions.

METHODS: We analysed anonymised electronic health records from a south London catchment area. We included patients aged ≥60 years at first recorded depression diagnosis with a dementia diagnosis. LL-DTD was defined as inadequate response to ≥2 antidepressant trials. Dementia diagnoses were classified as Alzheimer's disease (AD), vascular dementia (VD), mixed AD/VD, dementia with Lewy bodies (DLB), or other/unspecified dementia. Around the index depressive episode, we captured sociodemographics, depressive symptoms, physical comorbidity, and medication indicators. We used multivariate logistic regression to examine cross-sectional correlates distinguishing dementia subtypes (with AD as reference) within the LL-DTD and dementia sample. We conducted stratified analyses comparing non-AD versus AD dementia by the temporal order of dementia and depression diagnoses.

RESULTS: Among 890 older adults with LL-DTD and dementia, AD was the most common subtype (33.9%), followed by mixed AD/VD (22.5%), VD (22.2%), other/unspecified dementia (15.2%), and DLB (6.2%). Depressive symptom profiles and psychotropic treatment history were broadly similar across subtypes. Compared with AD, VD was associated with greater functional impairment, while greater physical comorbidity burden was more evident in VD and mixed AD/VD.

DISCUSSION: Somatic multimorbidity and functional impairment provided the clearest clinical separation between subgroups, while depressive symptom patterns and medication exposure appeared largely non-specific across dementia subtypes. This underscores the importance of multimorbidity and physical health burden in understanding heterogeneity of dementia outcomes in LL-DTD.},
}

@article {pmid42158310,
year = {2025},
author = {Jain, SK and Sharma, S and Singh, VK and Matreja, PS},
title = {Transplantation of human glial cells into murine brains: A systematic review of efficacy and safety in neurodegenerative disorders.},
journal = {Current journal of neurology},
volume = {24},
number = {2},
pages = {154-167},
pmid = {42158310},
issn = {2717-011X},
abstract = {Background: Neurodegenerative diseases impact millions of individuals globally. Over the years, brain research has predominantly focused on neurons, but attention is now shifting to glial cells, the brain's support cells, which play a vital role in neurodegenerative disorders. Therefore, glial cell transplantation represents a groundbreaking treatment approach for various neurodegenerative disorders, with the potential to restore neuronal function. We evaluated the evidence on the therapeutic effectiveness of human glial cell transplantation in neurodegenerative disorders. Methods: The literature review was performed in PubMed, Scopus, and Web of Science from 2000 to 2024. The authors independently reviewed the screened articles. The study outcomes on cell differentiation, long survival restoration of neuron function, and adverse outcomes were analyzed. Results: Study results highlight promising findings, including astrocytes improving motor function and slowing disease progression in neurodegenerative animal models through neurotrophic factor secretion and reduced inflammation. Similarly, microglia transplantation has demonstrated effectiveness in reducing α-synuclein toxicity in Parkinson's disease (PD), removing amyloid-β plaques in Alzheimer's disease (AD) models, and enhancing neuronal survival. Additionally, in demyelinating pathologies like multiple sclerosis (MS), oligodendrocyte transplantation promotes remyelination, restoring axonal conduction and enhancing functional outcomes. Cografting astrocytes with neuro progenitor cells significantly improved dopamine neuron engraftment and survival for at least 6 months post-transplantation. Conclusion: The transplantation of human glial cells offers promising therapeutic potential for neurodegenerative disorders, improving neuronal survival, restoring damaged circuits, and reducing disease progression.},
}

@article {pmid42159155,
year = {2026},
author = {Cummings, JL and Atri, A and Sano, M and Zetterberg, H and Scheltens, P and Knop, FK and Johannsen, P and Wichmann, CA and Abschneider, RM and Leon, T and Taylor, J and Feldman, HH},
title = {Plain language summary: the evoke(+) studies of semaglutide for early Alzheimer's disease.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/17582024.2026.2666332},
pmid = {42159155},
issn = {1758-2032},
}

@article {pmid42159271,
year = {2026},
author = {Shi, J and Du, Y and Wang, H and Zhang, N and Chen, W and Ni, J and Lu, X and Sun, Y and Wang, G and Liu, J and Zhang, W and Wei, M and Li, T and Zhou, B and Li, F and Wei, C and Yao, L and Xie, H and Tian, J and , },
title = {A paradigm of the diagnosis and treatment for the whole process of Alzheimer's disease.},
journal = {Annals of medicine},
volume = {58},
number = {1},
pages = {2672193},
doi = {10.1080/07853890.2026.2672193},
pmid = {42159271},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; *Medicine, Chinese Traditional/methods ; Biomarkers ; Disease Progression ; Early Diagnosis ; Severity of Illness Index ; Practice Guidelines as Topic ; },
abstract = {INTRODUCTION: The clinical management of Alzheimer's disease (AD) is still constrained by the fact that its incompletely understood pathogenesis, difficulty in early diagnosis and the limited long-term treatment benefits so far. This article summarizes a regional perspective on the diagnosis and treatment of AD from the Alzheimer's Disease Chinese (ADC) guideline working group, aiming to improve the whole-process management of AD.

DISCUSSION: The article presents a comprehensive overview of a proposed diagnostic and therapeutic paradigm for AD, consisting of a three-dimensional diagnostic framework and a sequential therapy concept. Crucially, while biological biomarkers of AD are present at all stages, they may be unrelated to clinical severity. To address this, the diagnostic framework combines core clinical criteria with early-changing biomarkers, syndrome staging and traditional Chinese medicine (TCM)-based pattern phenotyping. This integrated, simplified and practical approach enhances diagnostic certainty and its correlation with clinical severity. This sequential therapy is a stage-adaptive treatment plan adjusted according to the disease progression, utilizing a dynamic, multi-target combination therapy. Unlike the existing unchanging single-target therapies, this approach provides specific mechanistic interventions tailored to each stage to prolong efficacy and delay disease progression.

CONCLUSIONS: This paradigm provides a whole-process, stage-oriented approach to AD diagnosis and management that may improve translational relevance, clinical applicability and continuity of care in real-world settings. Future cohort-based validation studies are needed to confirm its diagnostic performance and clinical benefits, and to refine its implementation.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
*Medicine, Chinese Traditional/methods
Biomarkers
Disease Progression
Early Diagnosis
Severity of Illness Index
Practice Guidelines as Topic

@article {pmid42159313,
year = {2026},
author = {Tajika, A and Omae, K and Sahker, E and Luo, Y and Takekita, Y and Furukawa, TA},
title = {Public acceptance and expectations for Lecanemab: Insights from a Smallest Worthwhile Difference study.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.70082},
pmid = {42159313},
issn = {1440-1819},
abstract = {AIM: To determine the smallest worthwhile difference (SWD) for lecanemab, a disease-modifying drug for Alzheimer's disease (AD), among the general Japanese population using a benefit-harm trade-off method.

METHODS: We conducted an online survey with 658 participants to evaluate their preferences for the treatment effect of lecanemab, given its associated risks and high cost. We calculated SWD as the minimum required increase in the possibility of maintaining cognitive function (relative to the 50% without lecanemab) that patients would accept in exchange for the burdens of treatment (adverse effects, costs, other inconveniences). We examined the median SWD for two scenarios: a family member (SWD-families) and others (SWD-others), and analyzed subgroup differences.

RESULTS: The median SWD revealed a 15% increase for SWD-families and SWD-others. This value exceeds the drug's actual efficacy of an 8% increase. Notably, 17% of respondents reported zero SWD, driven by an intense fear of AD and possibly high expectations from media coverage. Including these participants, nearly half of the respondents considered the current effect worthwhile. No noticeable difference was found between the SWD-families and SWD-others.

CONCLUSION: Based on Japanese clinical scenarios, the public's median expectation for lecanemab exceeds its efficacy, though its current benefit remains acceptable to nearly half the population. These findings underscore that the SWD is shaped by psychological drivers, including fear and hope, rather than just reasoned evaluation. Clinicians must manage these expectations, accounting for highly heterogeneous treatment preferences. Future research should account for emotional factors that can overshadow a rational assessment of treatment value.},
}

@article {pmid42160117,
year = {2026},
author = {Chen, H and Wang, T and Xia, K and Li, X and Yao, X and Huang, W},
title = {Emerging Nanoreactors for Precision Disease Treatment: From Principles to Biomedical Applications.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e73859},
doi = {10.1002/smll.73859},
pmid = {42160117},
issn = {1613-6829},
support = {BK20251864//Basic Research Program of Jiangsu/ ; 62288102//Natural Science Foundation of China/ ; //Disciplinary Fund of the School of Pharmaceutical Sciences/ ; 20250285//Nanjing Tech University Teaching Reform Project/ ; },
abstract = {Inspired by natural cellular compartments, nanoreactors are spatially confined nanostructures that precisely regulate chemical and biological reactions and act as high-performance catalytic nanocontainers. Multifunctional integration of these systems surmounts the inherent limitations of conventional therapeutic modalities. This review focuses on recent breakthroughs in organic and organic-inorganic hybrid nanoreactors, highlighting three core effects: (1) the spatial confinement effect, which elevates the reactant concentration, accelerates mass transfer, lowers activation energy, modulates electronic states, and boosts reaction rates by orders of magnitude; (2) the synergistic effect of active sites, which enables efficient cascade reactions via spatially segregated or hierarchical catalytic architectures; (3) the stimuli-responsive effect, which dynamically controls catalysis and cargo release under endogenous (pH, enzymes, ROS) or exogenous (light, temperature) cues. Typical nanoreactors (liposomes, polymeric micelles/vesicles, mesoporous silica, protein cages, and organic-inorganic hybrids) are systematically discussed regarding structural merits and biomedical applications in treating diabetes, rheumatoid arthritis (RA), chronic wound healing, cancer, and Alzheimer's disease (AD). Current challenges and future perspectives are also addressed. Intelligent nanoreactors are expected to offer immense potential for disease diagnosis and therapy.},
}

@article {pmid42160848,
year = {2026},
author = {Zheng, M and Yang, M and Su, W and Tian, L and Gao, W},
title = {Targeting microglia: A new strategy for the treatment of Alzheimer's disease.},
journal = {Journal of neuroimmunology},
volume = {418},
number = {},
pages = {578966},
doi = {10.1016/j.jneuroim.2026.578966},
pmid = {42160848},
issn = {1872-8421},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.},
}

@article {pmid42160956,
year = {2026},
author = {Yan, Y and Hu, D and Kong, L and Li, K and Su, J and Wu, Y and Zhan, H and Zhang, H and Sun, Y and Dou, X and Huang, P and Zhou, J},
title = {Reductions in neuropsychiatric symptoms after lecanemab treatment and their associations with imaging markers of β-amyloid clearance.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100600},
doi = {10.1016/j.tjpad.2026.100600},
pmid = {42160956},
issn = {2426-0266},
abstract = {BACKGROUND: Anti-amyloid-β (Aβ) therapies can slow cognitive decline and reduce cerebral amyloid burden in Alzheimer's disease (AD). Neuropsychiatric symptoms (NPS) are highly prevalent across the disease course and substantially contribute to disability and caregiver burden. However, whether Aβ clearance translates into improvements in NPS remains unclear.

METHOD: We enrolled 144 individuals with AD-related mild cognitive impairment or AD dementia who received intravenous lecanemab infusions. Standardized clinical rating scales, including the Neuropsychiatric Inventory, and amyloid PET were assessed at baseline (V0), 6 months (V1), and 12 months (V2). Longitudinal changes in clinical function and amyloid burden were analyzed.

RESULTS: Lecanemab treatment was associated with robust reductions in amyloid PET biomarkers and significant short-term reductions in NPS scores in patients who completed follow-up. Longitudinal analyses showed that reductions in total NPI scores were significantly associated with amyloid-β clearance in the insular cortex. Reductions in the hyperactivity subsyndrome were associated with amyloid reduction across a broader network, including the frontal and temporal lobes, striatum, and insular cortex.

CONCLUSIONS: In this real-world cohort, lecanemab was associated with short-term reductions in NPS. Changes in NPS severity were linked to regional amyloid-β clearance.},
}

@article {pmid42161225,
year = {2026},
author = {McNamara, O and Delany, T and Kwakowsky, A},
title = {Bumetanide as a potential treatment for neurodegenerative and neurodevelopmental disorders: A systematic review.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {200},
number = {},
pages = {119533},
doi = {10.1016/j.biopha.2026.119533},
pmid = {42161225},
issn = {1950-6007},
abstract = {Neurological disorders represent a major global health burden, affecting an estimated 3.4 billion individuals worldwide. Bumetanide, a clinically approved loop-diuretic and antagonist of the Na[+] -K[+]-Cl[-] cotransporter NKCC1, has recently emerged as a candidate for repurposing in the treatment of neurological disorders. Disrupted excitation-inhibition balance, driven in part by depolarizing GABAA receptor signaling resulting from altered chloride homeostasis, has been implicated across multiple neurodegenerative and neurodevelopmental conditions. This systematic literature review evaluated preclinical and clinical evidence for the efficacy of bumetanide across a range of neurological disorders, including Alzheimer's, Parkinson's, and Huntington's disease, autism spectrum disorder, schizophrenia, tuberous sclerosis, fragile X syndrome, Down syndrome, and Angelman syndrome. Across in vivo and ex vivo models, bumetanide frequently restored hyperpolarizing GABAergic activity and attenuated behavioral and cognitive abnormalities, although translational relevance is constrained by limited central nervous system penetration following systemic administration. Clinical evidence mainly comes from autism spectrum disorder, where some studies have reported modest improvements in behavioral outcomes and measurable neurophysiological changes, although findings remain inconsistent. Collectively, these findings suggest that NKCC1 inhibition represents a mechanistically relevant but clinically unproven therapeutic strategy. Further research is required to clarify the cellular mechanisms underlying bumetanide responsiveness, optimize delivery to the central nervous system, and identify biomarkers to stratify patients most likely to respond to treatment.},
}

@article {pmid42161327,
year = {2026},
author = {Vallikivi, JK and Kooyman, M and , and Kirby, J and Nigel Leigh, P and Iacoangeli, A and Al-Chalabi, A and Al Khleifat, A},
title = {CYP2D6 variants in amyotrophic lateral sclerosis: an association study of risk and survival.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag178},
pmid = {42161327},
issn = {1460-2156},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited therapeutic options. Riluzole remains the only widely available disease-modifying treatment for ALS, yet its survival benefit is modest and likely to vary substantially between patients. Cytochrome P450 2D6 (CYP2D6), is a highly polymorphic enzyme that contributes to interindividual variability in the metabolism of many drugs. CYP2D6 is also expressed in the brain, and experimental and translational studies indicate that brain CYP2D activity can influence local metabolism of neuroactive compounds. Accordingly, CYP2D6 poor function variants have been examined as susceptibility modifiers in the development of other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease, with heterogenous evidence; however, the role of CYP2D6 in ALS has not been established.},
}

@article {pmid42161537,
year = {2026},
author = {Fernández-Romero, L and Díez-Cirarda, M and Delgado-Alonso, C and Cabrera-Martin, MN and González-Rosa, JJ and Sanz-Nieto, C and Pérez-Macías, N and Balugo, P and Gómez-Ruiz, N and Matias-Guiu, J and Portolés-Pérez, A and Matias-Guiu, JA},
title = {Long-term effect of transcranial magnetic stimulation and transcranial electrical stimulation in primary progressive aphasia: study protocol for a randomised, double-blind clinical trial (RECONNECT-PLUS).},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e112999},
doi = {10.1136/bmjopen-2025-112999},
pmid = {42161537},
issn = {2044-6055},
mesh = {Humans ; Double-Blind Method ; *Transcranial Direct Current Stimulation/methods ; *Transcranial Magnetic Stimulation/methods ; *Aphasia, Primary Progressive/therapy ; Female ; Aged ; *Language Therapy/methods ; Male ; Randomized Controlled Trials as Topic ; Treatment Outcome ; Middle Aged ; },
abstract = {INTRODUCTION: Primary progressive aphasia (PPA) is a neurodegenerative syndrome associated with Alzheimer's disease and frontotemporal degeneration. Non-invasive brain stimulation (NIBS) is a promising treatment, especially associated with language therapy, but comparative efficacy and long-term effects between the different techniques (transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)) remain unknown. The present study aims to investigate the effects of non-invasive brain stimulation, alone or associated (tDCS/TMS/tDCS plus TMS) combined with language therapy delivered during a period of 6 months, in the progression of language impairment in PPA, compared with sham stimulation combined with language therapy.

METHODS AND ANALYSIS: The study is a randomised, double-blinded, parallel, sham-controlled clinical trial. Patients with PPA in early stages (global Clinical Dementia Rating equal to or less than 1) are eligible. They are to be randomised to one of the four treatment arms of the study (active tDCS-active TMS, active tDCS-sham TMS, sham tDCS-active TMS, sham tDCS-sham TMS). All patients will receive language therapy immediately after each session of NIBS, for 6 months. The primary outcome is the Mini-Linguistic State Examination. The secondary outcomes are naming of trained items, Addenbrooke's Cognitive Examination, Interview for Deterioration in Daily Living Activities, Clinical Dementia Rating including behaviour and language domains, Neuropsychiatric Inventory and regional brain metabolism. Exploratory substudies will be conducted including blood biomarkers, quantitative electroencephalography and spontaneous speech assessment.

ETHICS AND DISSEMINATION: The study is registered (ClinicalTrials.gov: NCT07158216) and approved by the Ethics Committee of the Hospital Clinico San Carlos (code 25/309-IC_P_CE). Patients will be enrolled after signing an informed consent form. Study outcomes will be disseminated through presentations at scientific conferences, publications in peer-reviewed journals and other academic forums.

TRIAL REGISTRATION NUMBER: NCT07158216.},
}

Humans
Double-Blind Method
*Transcranial Direct Current Stimulation/methods
*Transcranial Magnetic Stimulation/methods
*Aphasia, Primary Progressive/therapy
Female
Aged
*Language Therapy/methods
Male
Randomized Controlled Trials as Topic
Treatment Outcome
Middle Aged

@article {pmid42161925,
year = {2026},
author = {Kim, DY and Kim, SM and Lee, C and Han, IO},
title = {O-GlcNAcylation reprograms microglial inflammatory states and attenuates Alzheimer's disease pathology.},
journal = {Cell death & disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41419-026-08862-3},
pmid = {42161925},
issn = {2041-4889},
support = {RS-2024-00346770//National Research Foundation of Korea (NRF)/ ; },
abstract = {Chronic neuroinflammation, primarily driven by microglia, is a hallmark and key contributor to Alzheimer's disease (AD) progression. O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of cellular stress and inflammation, yet its role in microglial activation in AD remains unclear. We observed that hippocampal tissue from AD patients exhibits a marked reduction in O-GlcNAcylation, accompanied by enhanced pro-inflammatory M1 microglial polarization, elevated NF-κB signaling, and NLRP3 inflammasome activation. In an LPS-induced neuroinflammation model exhibiting AD-relevant inflammatory and cognitive features, as well as in in vitro microglial cultures, LPS exposure led to a pronounced decrease in O-GlcNAcylation, particularly within Iba1-positive microglia. Systemic or in vitro treatment with glucosamine (GlcN) effectively restored O-GlcNAc levels, suppressed M1-associated inflammatory pathways, and promoted an anti-inflammatory M2 phenotype. Mechanistically, GlcN enhanced O-GlcNAcylation of NF-κB subunits p65 and c-Rel, limiting their nuclear translocation and downstream pro-inflammatory gene expression. Notably, GlcN treatment ameliorated LPS-induced memory deficits and neuronal loss in mice. Collectively, these findings suggest that O-GlcNAcylation acts as a modulatory regulator of microglial activation and neuroinflammation in AD, and that enhancing O-GlcNAcylation may represent a potential therapeutic strategy to preserve immune homeostasis and neuronal integrity.},
}

@article {pmid42162073,
year = {2026},
author = {Zamani, NISM and Hamezah, HS and Mediani, A and Ghazali, M and Sadikan, MZ and Jam, FA},
title = {Selective elimination of amyloid-β-induced senescent neuroblastoma cells by Moringa oleifera leaf extract.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-53311-y},
pmid = {42162073},
issn = {2045-2322},
support = {Fundamental Research Grant Scheme (FRGS/1/2024/SKK10/MUCM/02/1)//Ministry of Higher Education, Malaysia/ ; (MUCM-MRB/001/2024)//MUCM-MRB joint seed grant/ ; },
abstract = {Accumulation of senescent cells (SnCs) in the ageing brain contributes to Alzheimer's disease (AD) progression by secreting a senescence-associated secretory phenotype (SASP) that exacerbates neuroinflammation and neurodegeneration. Senolytic agents that selectively eliminate SnCs have emerged as a potential therapeutic strategy; however, safer natural alternatives remain underexplored. In this study, we aimed to investigate the senolytic potential of Moringa oleifera leaf extract (MOL) in an in vitro AD-senescence model using SH-SY5Y cells exposed to amyloid-β (Aβ1-42) oligomers. SH-SY5Y cells exposed to 20 µM Aβ oligomers exhibited a senescent phenotype, characterised by increased senescence-associated β-galactosidase (SA-β-gal) positivity and upregulated nuclear expression of p21, p16, and γH2AX. Treatment with 300 µg/mL MOL significantly reduced the number of cells expressing senescence-associated molecular markers and induced apoptosis in SnCs, while attenuating the secretion of pro-inflammatory SASP cytokines, including IL-8 and TNF-α. Overall findings suggest that MOL extract preferentially targets SnCs and mitigates SASP-associated inflammation. These results support the potential of MOL as a natural compound with senolytic activity and provide a foundation for further development into its therapeutic relevance in AD.},
}

@article {pmid42162487,
year = {2026},
author = {Singh, A and Denkinger, MN and Leuzy, A and Dieckhoff, K and Liu, J and Marques, TM and Monuki, E and Stark, C and Grill, JD and Hom, C and Sultzer, D and Doran, E and Lott, I and Wood, K and Gawronski, B and Gonzalez, L and Choudhury, P and Atri, A and Beach, TG and Serrano, GE and Sajjadi, SA and Van Keuren-Jensen, K and Reiman, EM and Head, E and Ashton, NJ},
title = {A plasma protein signature for cerebral amyloid angiopathy.},
journal = {Acta neuropathologica},
volume = {151},
number = {1},
pages = {},
pmid = {42162487},
issn = {1432-0533},
support = {U24 NS072026/NS/NINDS NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; contract 211002//Arizona Department of Health Services/ ; contracts 4001, 0011, 05-901 and 1001//Arizona Biomedical Research Commission/ ; },
mesh = {Humans ; *Cerebral Amyloid Angiopathy/blood/pathology/diagnosis ; Female ; Male ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Middle Aged ; Alzheimer Disease ; Cohort Studies ; },
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the deposition of amyloid-β (Aβ) in the walls of leptomeningeal and cortical blood vessels that increases risk of intracerebral hemorrhages and progressive cognitive decline. More than 90% of individuals with Alzheimer's disease (AD) exhibit some level of CAA. Notably, in the new era of disease-modifying treatments for AD, CAA is a significant risk factor for amyloid-related imaging abnormalities (ARIA), an adverse event associated with anti-amyloid treatments. Therefore, there is great need for accessible, reliable and accurate in vivo biomarkers (e.g., blood-based) to improve antemortem identification of CAA that would improve risk stratification and reduce symptomatic ARIA. In this study, we employed the Nucleic Acid-Linked Immuno-Sandwich Assay (NULISA™) central nervous system panel for exploratory biomarker quantification in antemortem plasma of participants with neuropathological assessments for CAA from the Banner Sun Health Research Institute Brain and Body Donation Program (N = 251) and independently validated in the University of California Irvine Alzheimer Disease Research Center cohort (N = 110). We evaluated the differential protein expression in antemortem plasma sample taken < 5 years (mean 1.76 ± 1.3) from death using a logistic regression model. We further compared multi-biomarker models and found that a combination of CRP, IL4, CCL11, NPY and PDLIM5, plus demographic covariates showed an area under the curve (AUC) of 0.90 (95% CI 0.86-0.94) to identify neuropathologically confirmed CAA in the discovery cohort. In our independent replication, the antemortem plasma signature performed better than the basic demographics model showing a potential to predict CAA. The exploration and validation in antemortem plasma indicate that a multi-analyte panel, when combined with in vivo blood biomarkers for AD pathology, may be capable of identifying the presence of CAA and could have an meaningful impact on the clinical evaluation of patients under the investigation for cognitive decline. Further developments in biomarkers for this condition are crucial so that CAA identification could inform treatment decisions by highlighting ARIA risk.},
}

Humans
*Cerebral Amyloid Angiopathy/blood/pathology/diagnosis
Female
Male
Aged
Biomarkers/blood
Aged, 80 and over
Middle Aged
Alzheimer Disease
Cohort Studies

@article {pmid42162953,
year = {2026},
author = {Karthivashan, G and Wang, S and Wu, Q and Dahal, A and Li, X and Galleguillos, D and Sipione, S and Thinakaran, G and Kar, S},
title = {Native PLGA nanoparticles attenuate disease pathology via multiple pathways in 5xFAD Alzheimer's model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71348},
doi = {10.1002/alz.71348},
pmid = {42162953},
issn = {1552-5279},
support = {MOP-84480//CIHR/Canada ; PJT-175090//CIHR/Canada ; //Alzheimer Society of Alberta and Northwest Territories/ ; RF1AG077610//National Institute on Aging, National Institutes of Health/ ; RF1AG079141//National Institute on Aging, National Institutes of Health/ ; //Ballermann Translational Research Fellowship/ ; //SynAD postdoctoral fellowships/ ; },
mesh = {*Alzheimer Disease/pathology/drug therapy/metabolism ; Animals ; *Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology ; *Nanoparticles/administration & dosage ; Mice ; *Amyloid beta-Peptides/metabolism/drug effects ; Disease Models, Animal ; Male ; Mice, Transgenic ; Brain/pathology/metabolism/drug effects ; },
abstract = {INTRODUCTION: Elevated amyloid beta (Aβ) levels and aggregation contribute to neurotoxicity and development of Alzheimer's disease (AD), the leading cause of dementia in the elderly. While we reported that native poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, clinically used in drug delivery, suppress Aβ aggregation/toxicity, their effects in adult 5xFAD mice with advanced Aβ pathology remain unknown.

METHODS: We evaluated the effects of native PLGA in 8-month-old male 5xFAD mice via chronic intracerebroventricular (ICV) infusion using mini osmotic pumps. Cognitive function, amyloid level/burden, synaptic integrity, and neurodegenerative events were assessed along with transcript levels in brain tissues using bulk RNA sequencing (RNA-seq).

RESULTS: PLGA treatment reversed cognitive deficits, reduced Aβ levels/deposits, and attenuated neurodegenerative events. These effects were associated with modulation of Aβ production, oxidative stress, and lysosomal Aβ clearance. RNA-seq revealed transcriptional changes related to vesicle trafficking, immune activity, and redox regulation.

DISCUSSION: Native PLGA, by targeting different facets of the Aβ axis, offer unique therapeutic potential in treating AD-related pathology.},
}

*Alzheimer Disease/pathology/drug therapy/metabolism
Animals
*Polylactic Acid-Polyglycolic Acid Copolymer/administration & dosage/pharmacology
*Nanoparticles/administration & dosage
Mice
*Amyloid beta-Peptides/metabolism/drug effects
Disease Models, Animal
Male
Mice, Transgenic
Brain/pathology/metabolism/drug effects

@article {pmid42162968,
year = {2026},
author = {Reyna, NC and Hamilton, DA},
title = {Effects of Corticotropin-Releasing Factor 1 Receptor Antagonism on In Vivo Dentate Gyrus Long-Term Potentiation in the TgF344-AD Rat Model of Alzheimer's Disease.},
journal = {Hippocampus},
volume = {36},
number = {3},
pages = {e70103},
doi = {10.1002/hipo.70103},
pmid = {42162968},
issn = {1098-1063},
support = {P20AG068077/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Long-Term Potentiation/drug effects/physiology ; *Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism ; *Dentate Gyrus/drug effects/physiopathology ; *Alzheimer Disease/physiopathology/drug therapy/pathology/genetics ; *Pyrroles/pharmacology ; *Pyrimidines/pharmacology ; Disease Models, Animal ; CRF Receptor, Type 1 ; Rats, Transgenic ; Male ; Rats ; Rats, Inbred F344 ; Excitatory Postsynaptic Potentials/drug effects/physiology ; },
abstract = {Alzheimer's disease (AD) is characterized by irreversible neurobiological deterioration and cognitive impairment. AD patients exhibit stress system abnormalities including upregulation of the corticotropin releasing factor type 1 receptor (CRF1) and elevated cortisol. Psychological distress increases the likelihood of AD diagnosis and hastens neurocognitive decline. Administration of the CRF1 antagonist, Antalarmin, reduces AD pathogenesis and anxiety-like behavior in models of AD. Motivated by these observations, the current study examined the potential contributions of CRF1 to altered synaptic plasticity in AD neuropathology and stress in the TgF344-AD rat model. In vivo electrophysiological recordings to assess long-term potentiation (LTP) in the perforant pathway to dentate gyrus synapses were performed in aged transgenic rats and wild-type (WT) controls (2-2.5 years). TgF344-AD rats had abnormal LTP measures of field excitatory post-synaptic potentials (fEPSP) and population spikes (PS). Treatment with Antalarmin did not alter LTP measures in TgF344-AD or WT rats. These observations indicate that LTP in TgF344-AD rats is reduced compared to WT rats and that acute treatment with a CRF1 antagonist did not rescue LTP deficits. Future research should further examine the mechanism of CRF1 in AD and implications of agonism or direct infusions of Antalarmin in vivo.},
}

Animals
*Long-Term Potentiation/drug effects/physiology
*Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors/metabolism
*Dentate Gyrus/drug effects/physiopathology
*Alzheimer Disease/physiopathology/drug therapy/pathology/genetics
*Pyrroles/pharmacology
*Pyrimidines/pharmacology
Disease Models, Animal
CRF Receptor, Type 1
Rats, Transgenic
Male
Rats
Rats, Inbred F344
Excitatory Postsynaptic Potentials/drug effects/physiology

@article {pmid42163277,
year = {2026},
author = {Lee, HJ and Seok, J and Kang, S and Oh, S and Hwang, JW and Kim, YJ and Seo, J and Hoe, HS},
title = {The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03855-7},
pmid = {42163277},
issn = {1742-2094},
support = {RS-2024-00357857//NRF/ ; RS-2024-00343370//KDRC/ ; H0501-25-1001//NIPA/ ; 20190058//Whanin Pharm Co., Ltd/ ; 26-BR-02-04, 26-BR-05-01, and 26-BR-06-01//KBRI funded by the Ministry of Science, ICT & Future Planning/ ; RS-2026-25492172//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated.

METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays.

RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation.

CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.},
}

@article {pmid42163384,
year = {2026},
author = {Hsu, JL and Huang, SY and Wu, HC and Lin, KJ and Huang, KL and Huang, CC and Kim, S and Hsiao, IT},
title = {A clinically feasible framework to estimate tau pathology and clinical-biological discordance in the Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02083-8},
pmid = {42163384},
issn = {1758-9193},
support = {MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; MOST 111-2314-B-182A-036-MY2, NSTC 112-2628-B-182-007-MY3, NSTC-113-2314-B-182-042-MY2, NSTC-114-2314-B-182-043, NSTC 114-2314-B-182A-061-MY3//National Science and Technology Council/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; CORPG3P0281, CORPG3P0291, BMRP488//Chang Gung Memorial Hospital Research Fund/ ; },
abstract = {BACKGROUND: Tau positron emission tomography (PET) is critical for biological staging and treatment stratification in Alzheimer's disease (AD), particularly in the era of anti-amyloid therapies where lower tau burden predicts greater clinical benefit. However, tau PET remains costly and inaccessible in many clinical settings. We aimed to develop and validate a clinically feasible framework to estimate global and regional tau burden using routinely available amyloid PET and clinical measures, aligned with the 2024 Alzheimer's Association (AA-2024) diagnostic framework, and to characterize clinical-biological discordance across the AD continuum.

METHODS: We conducted a cross-sectional study of 229 individuals spanning cognitively unimpaired, mild cognitive impairment, and dementia stages who underwent [[18]F]florbetapir amyloid PET, [[18]F]florzolotau tau PET, structural MRI, and cognitive assessment. Amyloid burden was quantified using the Centiloid (CL) scale (A+ defined as CL > 20). Tracer-specific tau thresholds for global and Braak-stage volumes were derived using two-component Gaussian mixture modeling. Logistic regression models incorporating CL, age, Mini-Mental State Examination (MMSE), and medial temporal lobe (MTL) volume were developed to classify high global tau burden and neocortical tau involvement. Among amyloid-positive individuals, biological staging was compared with clinical stage to assess discordance patterns.

RESULTS: Global and regional tau burden increased stepwise across clinical severity and amyloid strata. High global tau burden was uncommon in individuals with CL 21-60 (6.1%) but increased in CL 61-100 (22.6%) and > 100 (36.2%). A multivariable model integrating CL, age, MMSE, and relative MTL volume demonstrated good discrimination for high global tau burden (AUC = 0.87) and neocortical involvement (AUC = 0.84). Model robustness was confirmed by bootstrap resampling. Among amyloid-positive participants, 53.1% exhibited clinical-predominant AD, characterized by older age and higher cardiovascular risk despite relatively modest tau burden, indicating substantial clinical-biological discordance.

CONCLUSION: Routinely obtainable amyloid PET and clinical measures can approximate global and topographical tau burden with good accuracy and identify frequent clinical-biological discordance within the AD spectrum. This scalable framework provides a practical surrogate for tau PET in resource-limited settings and may support biological staging, therapeutic eligibility assessment, and precision treatment decision-making.},
}

@article {pmid42163678,
year = {2026},
author = {Jin, S and Liu, D and Ouyang, J},
title = {An Investigation of the Neurotoxic Mechanisms of Benzo[a]pyrene in Alzheimer's Disease Using an Integrated Approach of Network Toxicology and Machine Learning.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X447239260407111712},
pmid = {42163678},
issn = {1875-6190},
abstract = {INTRODUCTION: Benzo[a]pyrene (BaP) exposure is increasingly associated with the progression of Alzheimer's Disease (AD), yet the specific molecular links remain poorly understood. This study utilizes an integrated computational framework, combining network toxicology, machine learning, and molecular dynamics simulations, to identify core biomarkers and elucidate the potential pathological interplay between BaP and AD.

METHODS: We began our analysis by identifying the intersection of targets and then created a Protein-Protein Interaction (PPI) Network to identify hub genes. To ensure accuracy, we selected final core molecular targets from the intersection of three distinct types of machine learning algorithms. To validate diagnostic value, immune cell infiltration data analysis was performed using the GSE138260 dataset. Finally, we used molecular docking and 100 ns dynamics to assess how BaP interacts with the core molecular target.

RESULTS: We identified four proteins associated with BaP and AD: CASP3 (Caspase 3), HTT (Huntingtin), TH (Tyrosine Hydroxylase), and PARK7 (DJ-1). These proteins signal neuronal apoptosis and neuro-immune dysregulation due to their involvement in pathways associated with these processes. The Receiver Operating Characteristic (ROC) analysis demonstrated strong diagnostic properties for these targets. Molecular docking data also showed BaP as the main target, with TH binding with a value of -10.02 kcal/mol. The stability of this BaP-TH complex was further confirmed by 100 ns molecular dynamics simulations.

DISCUSSION: The research reveals TH's critical effect on BaP-induced neurotoxicity. We also identify the potential molecular mechanisms contributing to Alzheimer's disease pathology via environmental exposure.

CONCLUSION: This research identifies several significant molecular interactions between BaP and AD. One major molecular target for BaP interaction with AD is tyrosine hydroxylase (TH). Our findings here create an opportunity for the development of therapeutics for the treatment of AD cases caused by exposure to environmental toxins.},
}

@article {pmid42163745,
year = {2026},
author = {Abdalla, EA and Fayed, AM and Hussein, MA and Abdel-Aziz, A and Mohamed, ZN},
title = {Multi-Target Neuroprotection of Salvia officinalis Aqueous Extract in a Scopolamine-Induced Model of Alzheimer's Disease: Comparative Efficacy Versus Donepezil.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128429239260312074215},
pmid = {42163745},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex, age-related, neurodegenerative disorder that involves cognitive deterioration, oxidative stress, and neuroinflammation. Symptomatic relief is limited with conventional treatments such as donepezil, sparking a significant interest in multi-target botanicals. We examined the neuroprotective effects of Salvia officinalis aqueous extract (SAGE) on a scopolamine-induced animal model of AD and the related molecular mechanisms regarding GABRA5α, GSK-3β, and pERK pathways.

METHODS: SAGE was characterized using phytochemical profiling and antioxidant assays. IC50 values were determined in vitro for inhibitor activity against GABRA5α and GSK-3β. In vivo experiments included assessment of behavior (Morris water maze), assays for oxidative stress and inflammation, gene expression studies by qPCR, and histopathology of hippocampal tissue. Efficacy versus donepezil was compared. Statistical significance was based on one-way ANOVA followed by Tukey's post-hoc test (p < 0.05) for robust comparisons between all treatment groups.

RESULTS: The SAGE had strong antioxidant abilities and was able to inhibit GABRA5α and GSK-3β in a target-specific way. SAGE treatment greatly enhanced spatial learning and memory, retained the redox equilibrium, decreased neuroinflammatory markers, and normalized AChE activity. Gene expression was found to modulate favourably for GABRA5α, GSK-3β and pERK. Histological findings confirmed neuronal preservation. In all parameters, SAGE was more effective than donepezil. The present findings demonstrated the therapeutic potential of SAGE's phenolics to mitigate oxidative cascades, including those suggested as contributing factors to AD pathology.

DISCUSSION: The superior multi-modal efficacy of SAGE over donepezil due to its phenolic-rich phytochemical profile and capacity to modulate oxidative, inflammatory, and neuronal pathways is demonstrated. This is encouraging, and additional studies should be conducted to investigate pharmacokinetics, mechanistic and clinical significance.

CONCLUSION: S. officinalis AE strongly protects the brain against scopolamine-induced AD-like neuropathology in a superior way over standard treatment via altered multi-targets. Its characteristics promote its further development as a natural therapeutic candidate for AD treatment. There are however constraints, such as nodescription of the pharmacokinetic profiling and no tau/Aβ quantification. Prospective studies with these endpoints and chronic dosing schedules should now address the issue of long-term effectiveness and safety.},
}

@article {pmid42164259,
year = {2026},
author = {Giorelli, M},
title = {Reframing Alzheimer's disease as a complex adaptive system: More than an amyloid beta-tau connection.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70256},
pmid = {42164259},
issn = {2352-8737},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia, but simple models focusing on amyloid beta and tau only partially explain its variability and limited success in treatment. Evidence from systems biology, neuroimmunology, connectomics, and computational modeling supports viewing AD as a complex adaptive system, a multiscale network in which genetic, molecular, cellular, vascular, and environmental factors interact in complex, non-linear ways over time. In this perspective, disease paths develop from feedback-driven instabilities that spread across different levels, while resilience and compensatory mechanisms influence individual outcomes. This new understanding has important implications: diagnostic approaches should shift from static lesion biomarkers to longitudinal, multimodal measures of network states; treatments should combine pharmacological, metabolic, vascular, inflammatory, cognitive, and neuromodulatory strategies; and adaptive, model-informed algorithms should customize the timing and dosage to each patient's unique dynamics. Recognizing the complexity enables earlier detection of critical tipping points, targeted reinforcement of resilience, and personalized intervention plans, shifting AD care from late-stage, single-target methods to precision network medicine.},
}

@article {pmid42164431,
year = {2026},
author = {Schuller, AJ and Hager, MR and Briggs, AM and Rocha, SM and Yanouri, OA and Smith, EJ and Hall, SE and Montrose, LB and Tjalkens, RB},
title = {Treadmill training induces sex-dependent changes in hippocampal epigenetic patterns and plaque-associated microglial morphology in aged TgF344 rats.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1805957},
pmid = {42164431},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder world-wide, characterized by progressive neuroinflammation, aberrant protein accumulation, and neuronal loss associated with cognitive decline. Although our understanding of the molecular mechanisms underlying AD pathogenesis has greatly increased in recent years, there remain limited treatment strategies and no cures for this disorder. Because of this, efforts have shifted toward identifying modifiable lifestyle factors which may decrease risk of onset or slow AD progression. One such approach which has shown promise in modulating the disease course is physical exercise. However, sex-specific effects of implementing such activity strategies in aged individuals after the onset of disease are less well studied. We sought to address this knowledge gap by characterizing hippocampal histopathology and DNA modification profiles of aged TgF344-AD rats following progressive treadmill-training. Reduced-representation bisulfite sequencing indicated 94 genes associated with differentially modified cytosines (DMCs) in exercised females (239 differentially modified regions, 54.6% hypermodified) and 87 DMC-associated genes in exercised males (216 differentially modified regions, 50.4% hypermodified) with unique functional enrichment for overrepresented pathways and protein interactions relevant to glial activation and synaptic plasticity. Using quantitative high-throughput slide scanning fluorescence microscopy we additionally examined this brain region for AD-relevant changes including neuronal and microglial density, microglial morphology, and accumulation of pathologic protein. This analysis revealed female-specific reductions in NeuN[+] and Iba1[+] cells in treadmill-trained animals, as well as sex- and exercise-dependent changes in plaque-associated microglial reactivity state. Together, these findings reveal that age of onset, biologic sex, and duration of physical exertion may be important factors in modulating the pathologic progression of AD.},
}

@article {pmid41975292,
year = {2026},
author = {Esmaeili, H and Mahdavi-Fikjvar, E and Poureshaghi, F and Moridi Farimani, M and Sonboli, A and Dastres, E and Behboudi, H and Mirjalili, MH},
title = {Variation in phytochemical profiles and anti-cholinesterase activity across wild Iranian populations of Leucojum aestivum L.: a conservation perspective.},
journal = {BMC plant biology},
volume = {26},
number = {1},
pages = {},
pmid = {41975292},
issn = {1471-2229},
abstract = {BACKGROUND: Leucojum aestivum L. (Amaryllidaceae) is a perennial bulbous species of high pharmaceutical importance, primarily recognized as a natural source of the alkaloid galantamine for Alzheimer’s disease treatment. Iranian L. aestivum populations (LAPs) may contain unique alkaloids with strong acetylcholinesterase (AChE) inhibitory effects, making them a conservation priority. To investigate phytochemical diversity and bioactivity, eight natural populations including LAP1 (Chahar Deh, Astaneh Ashrafieh); LAP2 (Baz Kia Gurab, Lahijan); LAP3 (Sangar); LAP4 (Chomesghal, Ziabar); LAP5 (Pinchah, Astaneh Ashrafieh); LAP6 (Chaboksar); LAP7 (Valiseh, Rudsar); and LAP8 (Vali Abad, Tonkabon) were sampled during the flowering stage. Galantamine, lycorine, total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity (FRAP and DPPH), and AChE inhibitory activity were quantified in bulbs and leaves.

RESULTS: The highest AChE inhibition was recorded in bulbs of LAP6 (IC50: 95.57 µg/ml) and LAP7 (IC50: 102.38 µg/ml), corresponding to elevated galantamine levels (20.31 and 24.92 mg/g dry extract, respectively), which showed a strong positive correlation (r = 0.880, p < 0.01). In contrast, LAP8 contained no detectable galantamine in bulbs but exhibited exceptionally high leaf lycorine content (107.91 mg galanthamine equivalent/g dry extract) and antioxidant capacity (FRAP: 90.71 µmol Fe²⁺/g DW; DPPH, IC₅₀: 95.10 µg/ml), alongside moderate AChE inhibition (IC50: 150.80 µg/ml in bulbs, 231.63 µg/ml in leaves). Leaf TPC (8.57–13.39 mg GAE/g DW) consistently exceeded bulb TPC (0.18–7.59 mg GAE/g DW). Cluster analysis grouped populations into three distinct classes: balanced alkaloid levels and antioxidant power (LAP1, LAP5, LAP6), lower alkaloid levels (LAP2, LAP3, LAP4), and high phenolic content and antioxidant power with relatively elevated alkaloid levels (LAP7, LAP8).

CONCLUSIONS: These findings demonstrated a strong linkage between alkaloid composition and bioactivity, highlighting the pharmaceutical potential of specific chemotypes and emphasizing the necessity of in situ conservation and ex situ cultivation for sustainable utilization and drug development targeting cholinesterase inhibition and antioxidant activity.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12870-026-08717-1.},
}

@article {pmid42151697,
year = {2026},
author = {Visentini, AE and Reichert, KP and Schetinger, MRC and Bottari, NB and Miron, VV and Castro, MFV and da Silveira, MV and Assmann, CE and Schirmann, AA and Morsch, VMM},
title = {Resveratrol as a potential natural compound to ameliorate cognitive impairment in aluminum-exposed mice: impacts on behavior, purinergic system, and brain inflammation.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {42151697},
issn = {1573-7365},
abstract = {UNLABELLED: Aluminum (Al[3+]) accumulates in the brain and has been linked to neurodegeneration. When combined with citrate, its absorption increase, raising the risk of neurodegenerative disorders such as Alzheimer’s disease. Resveratrol (RSV), a polyphenol with anti-inflammatory, antioxidant, and neuroprotective properties, has been associated with aging prevention by reducing oxidative stress. This in vivo study aimed to determine whether RSV could protect male Swiss mice from Al[3+]-induced cognitive impairment, alterations in purinergic signaling, and brain inflammation. The study was conducted using 60 animals treated with aluminum chloride (AlCl3 50 mg/Kg, gavage), citrate (AlCl3 50 mg/Kg + CIT 100 mg/Kg, gavage), and resveratrol (AlCl3 50 mg/Kg + RSV 100 mg/Kg, gavage), along with their respective Controls, for 30 days every 48 h. Behavioral assessments included the open field test, object recognition test, and Y-maze test to evaluate cognitive performance. Enzymatic activity of purinergic pathways and levels of receptors and inflammation-related molecules were also analyzed. AlCl3 and AlCl3 + CIT induced an inflammatory response in mice, as evidenced by the modulation of purinergic system enzymes associated with inflammation. Al[3+] intoxication also triggered behavior alterations, which was modulated by CIT and alleviated by RSV treatment. Western blot findings revealed that AlCl3 and AlCl3 + CIT altered protein levels of purinergic receptors (A1R, A2AR, and P2 × 7R), the inflammasome protein NLRP3, the pro-inflammatory cytokine IL-1β, and the neurotrophic factor BDNF. RSV counteracted the toxic effects of Al[3+], providing neuroprotection against its toxicity and presenting itself as a potential therapeutic candidate for cognitive deficits.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11011-026-01859-z.},
}

@article {pmid42152645,
year = {2026},
author = {Kishor, K and Arora, A and Yashika, and Yadav, S and Singh, A},
title = {Extracellular Vesicles in Alzheimer's Disease: Mechanisms, Immunotherapy Links, and Clinical Translation.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128464813260512100753},
pmid = {42152645},
issn = {1873-4286},
abstract = {Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction, neuroinflammation, and cognitive impairment. Although amyloid-β and tau continue to serve as core biomarkers and therapeutic targets, the clinical efficacy of recent biologic agents targeting amyloid has led to a new paradigm in AD treatment. Nevertheless, emerging data show that lipid metabolism is an important and well-established aspect of AD pathophysiology rather than a new theory. Lipid processing in microglia, astrocytes, and neurons is disrupted, leading to chronic inflammation, impaired amyloid clearance, mitochondrial dysfunction, and synaptic dysfunction. This review critically analyzes how lipid accumulation and lipid droplet biology contribute to Alzheimer's disease using cellular, animal, and human studies. Special focus is placed on enzymatic regulators such as DGAT2, cholesterol transport, and neuron-glia metabolic linkages. This review synthesizes existing mechanistic and translational data to emphasize lipid dysregulation as a complementary therapeutic target and potential biomarker axis that may improve current amyloid- and taudirected therapeutic strategies.},
}

@article {pmid42152660,
year = {2026},
author = {Younas, S and Badshah, I and Akbar, K and Al-Otaibi, JS and Khan, H},
title = {3-(2,4-Dimethylbenzylidene)-6-chloroindolin-2-one Alleviates Memory Impairment in D-Galactose-induced Alzheimer Like Pathology in a Mouse Model.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X434400260421062719},
pmid = {42152660},
issn = {1875-6190},
abstract = {INTRODUCTION: Oxidative stress and neuroinflammation are the main contributors to Alzheimer's disease (AD). The current study evaluated the neuroprotective efficacy of 3-(2,4- dimethylbenzylidene)-6-chloroindolin-2-one (DMO) against D-Galactose (GAL)-induced neuroinflammation, oxidative stress, and memory impairment in mice.

METHODS: Swiss Male albino mice weighing (25-30 g) were assigned to five experimental groups (n=6) (i) Normal group (received normal saline 0.9%) (ii) Control group (received GAL 100 mg/kg i.p) (iii) Standard group (received Donepezil 5 mg/kg + GAL 100 mg/kg i.p) (iv) Treatment group 1 (received DMO 5 mg/kg + GAL 100 mg/kg i.p) and Treatment group 2 (received DMO 10 mg/kg + GAL 100 mg/kg i.p) once daily for 8 weeks. After treatment, the mice were subjected to behavioral analysis, followed by sacrifice for further analysis.

RESULTS: DMO alleviated GAL-induced cognitive impairment as shown by the Morris water maze test (MWM), Y-maze, elevated plus maze (EPM), and open field (OF) test. Brain tissue histology showed reversal of distorted neuronal structures and decreased pyknosis upon DMO treatment. DMO also decreased the levels of Glutathione-S-Transferase (GST), reduced Glutathione (GSH), and catalase (CAT), concomitant with increased lipid peroxidase (LPO). Furthermore, levels of TNF-α and NF- ҡB, were significantly reduced in the DMO treatment groups as quantified by ELISA. In addition, Reverse transcription polymerase chain reaction (RT-PCR) showed a substantial decrease in the expression of β-amyloid and Tau protein.

DISCUSSION: The results showed that DMO inhibits D-gal induced oxidative stress, neuroinflammation and consequently alleviates memory impairment.

CONCLUSION: Our novel findings suggest that DMO could be a promising therapeutic modality for the treatment of brain aging-associated disorders.},
}

@article {pmid42152670,
year = {2026},
author = {Bjørklund, G and Izmailovich, M and Glushkova, N and Semenova, Y},
title = {Vitamin E in Alzheimer's Disease: A Perspective on Antioxidant Therapy.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673386940251024110821},
pmid = {42152670},
issn = {1875-533X},
abstract = {This study explores the relationship between vitamin E and Alzheimer's disease (AD), a neurodegenerative disorder characterized by cognitive decline, memory loss, and language impairment. Vitamin E is a fat-soluble antioxidant crucial in protecting cells from oxidative damage. The biochemistry and bioavailability of vitamin E are discussed, including its absorption, transport, and storage in the body. The section on interactions between vitamin E and other nutrients and herbals highlights how combining vitamin E supplements with other supplements or medications can affect its absorption, metabolism, and effectiveness. This study also discusses the potential therapeutic effects of vitamin E on AD, including its ability to reduce oxidative stress and inflammation, which are thought to play a role in the pathophysiology of AD. It explores the synergistic effects of vitamin E with pharmaceuticals and potential side effects, and covers the use of vitamin E in combination with other drugs for AD treatment, such as cholinesterase inhibitors and memantine, as well as the possible adverse effects of vitamin E supplementation. Overall, this study highlights the importance of vitamin E in preventing and managing AD and underscores the need for further research in this area.},
}

@article {pmid42152699,
year = {2026},
author = {Oba, GMJ and Sahu, R and Shah, K and Singh, AP},
title = {Interesting Potential Derivatives Based on the Coumarin Scaffold for the Treatment of Alzheimer's Disease.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575449515260428094401},
pmid = {42152699},
issn = {1875-5607},
abstract = {As the most common and deadly age-related neurodegenerative disease, Alzheimer's Disease (AD) affects the vast majority of elderly individuals. As such, new drugs are being produced, and their safety is still being assessed. Coumarin-based medications are among the most important pharmacophores in both natural and synthetic medicinal compounds. Targeting several essential receptors or enzymes, this six-membered aromatic heterocycle, linked by two oxygen atoms, has numerous therapeutic applications in research and offers many opportunities for future improvements in anti-Alzheimer's drugs. Several coumarin compounds have been shown to inhibit not just enzymes and receptors but also a wide range of additional targets involved in the battle against AD. The expansion of new derivatives based on coumarins in conjunction with other moieties for the treatment of AD is the current focus of research. In order to help scientists design effective drugs with the right pharmacological activity, this study sheds light on the current therapeutic expansion of coumarin-based derivatives as well as their synthesis methods.},
}

@article {pmid42152706,
year = {2026},
author = {Karayat, M and Kaushik, N and Paliwal, D},
title = {Scopoletin as a Potential Therapeutic Agent for Neurodegenerative Disorders: Mechanisms and Perspectives.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266399675251201111538},
pmid = {42152706},
issn = {1873-4294},
abstract = {Neurodegenerative diseases, such as Alzheimer's and Parkinson's, continue to pose significant challenges due to their complex aetiology and limited treatment options. Scopoletin, a naturally occurring coumarin found in a variety of medicinal plants, is being explored as a potential therapeutic agent because of its broad pharmacological profile. This review investigates scopoletin's neuroprotective potential, with particular emphasis on its antioxidant, anti-apoptotic, and cholinergic-regulating properties. It also highlights its ability to reduce oxidative stress, modulate neurotransmitter balance, and prevent protein aggregation, which are key pathological features of neurodegeneration. Despite promising preclinical findings, further research is required to establish its efficacy, optimise its bioavailability, and evaluate its safety in clinical settings. Overall, scopoletin demonstrates considerable potential as a neuroprotective compound, offering new avenues for the development of innovative therapeutics for neurodegenerative disorders. This comprehensive review aims to provide a foundation for future research and the advancement of scopoletin as a promising agent against neurodegeneration.},
}

@article {pmid42157023,
year = {2026},
author = {Rybicki-Kler, CI and Brooks, IAW and Jedrasiak-Cape, I and Deng, T and Avila, C and Brouns, E and Lekander, A and Ahmed, OJ},
title = {Reciprocal molecular and cellular cholinergic working memory impairments in Alzheimer's disease model mice.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71490},
doi = {10.1002/alz.71490},
pmid = {42157023},
issn = {1552-5279},
support = {R01MH129282/MH/NIMH NIH HHS/United States ; R34NS127101/NS/NINDS NIH HHS/United States ; P50NS123067/NS/NINDS NIH HHS/United States ; T32NS007222/NS/NINDS NIH HHS/United States ; T32NS076401/NS/NINDS NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; F31AG087629/AG/NIA NIH HHS/United States ; AARG-NTF-21-846572/ALZ/Alzheimer's Association/United States ; T32DC000011/DC/NIDCD NIH HHS/United States ; G102865/321033//Berger Endowment/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology ; Disease Models, Animal ; Mice ; *Memory, Short-Term/physiology ; Mice, Transgenic ; *Cholinergic Neurons/metabolism ; Receptor, Muscarinic M1/metabolism/genetics ; Humans ; Cerebral Cortex/metabolism ; Acetylcholine/metabolism ; *Memory Disorders ; },
abstract = {INTRODUCTION: The degeneration of basal forebrain cholinergic neurons is a key pathophysiological feature of Alzheimer's disease (AD). These cholinergic neurons target cortical neurons including those in the granular retrosplenial cortex (RSG) to facilitate essential cognitive functions. At the cellular level, acetylcholine supports working memory by inducing persistent firing that outlasts the stimulus, but how such cholinergic-induced persistent firing is altered in AD remains unknown.

METHODS: Using multiscale molecular and cellular analyses, we investigated neuron type-specific transcriptomic and physiological impairments of cholinergic persistent signaling in the RSG of 5xFAD mice.

RESULTS: Cholinergic inputs to RSG were reduced in 5xFAD mice. Expression of the Chrm1 gene encoding M1 muscarinic receptors was also reduced in RSG neurons, coupled with impaired cellular persistent firing.

DISCUSSION: The loss of M1 receptors suggests that allosteric M1 modulators being considered for treatment of AD symptoms may not be as effective on key cell types, necessitating further multiscale investigation.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology
Disease Models, Animal
Mice
*Memory, Short-Term/physiology
Mice, Transgenic
*Cholinergic Neurons/metabolism
Receptor, Muscarinic M1/metabolism/genetics
Humans
Cerebral Cortex/metabolism
Acetylcholine/metabolism
*Memory Disorders

@article {pmid42157276,
year = {2026},
author = {Krick, KE and Chalk, JL and Lykins, JT and Wang, HP and Ferguson, CA and Shahid, SS and Weekman, EM and Wilcock, DM},
title = {TNF inhibition differentially impacts regional Abeta immunotherapy efficacy in the humanized hAb[SAA] mouse model.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02084-7},
pmid = {42157276},
issn = {1758-9193},
support = {1RF1NS130834//Foundation for the National Institutes of Health/ ; },
abstract = {BACKGROUND: The FDA approval of amyloid beta (Aβ) targeting immunotherapies offered the first opportunity to clinically modify Alzheimer's disease progression and give patients back precious months in the course of disease progression. The administration of these therapeutics has uncovered a common side effect called Amyloid Related Imaging Abnormalities (ARIA). While often asymptomatic, these adverse events have potential to escalate, and their commonality has encouraged further studies to mitigate their incidence. Increases in immune activation are important in immunotherapy action, though heightened release of cytokines have also been shown in ARIA development. TNF has been shown in early studies to increase with immunotherapy administration and subsequent ARIA development and TNF itself has been implicated in blood brain barrier dysfunction which could contribute to hemorrhagic ARIA (ARIA-H) development.

METHODS: This study assessed hemorrhage outcomes in an aged mouse model using MRI and Prussian blue histology, explored transcriptomic and protein changes with NanoString nCounter and Meso Scale Discovery, and we performed immunohistochemical stains for microglia/macrophages, astrocytes, and pericyte changes.

RESULTS: In this study, we established ARIA-H pathology in a humanized mouse model (hAβ[SAA]) via chronic Aβ immunotherapy administration. We saw significant hemorrhagic lesions in our model, despite low levels of cortical cerebral amyloid angiopathy (CAA) suggesting a role for CAA as a risk factor for ARIA but potentially not its driver. We also explored the role of TNF in ARIA progression by inhibiting soluble TNF alongside immunotherapy administration as a potential combination therapeutic to address ARIA. With TNF inhibition, we saw a reduction of hemorrhages in the hippocampus, but not in the cortex, suggesting a regional effect. Further, we saw additional regional differences between the cortex and hippocampus with TNF inhibition including macrophage activation markers and amyloid levels, suggesting a differential role for TNF signaling in these areas and a potential heterogeneity of cellular responses in each region.

CONCLUSION: We induced ARIA without significant cortical CAA pathology and identified regional differences with TNF inhibition including a potential benefit of treatment in the hippocampus and possible detriment to pathology in the cortex.},
}

@article {pmid42157624,
year = {2026},
author = {Granberg, T and Blystad, I and Fällmar, D and Savitcheva, I and van Westen, D and Westman, E},
title = {[Brain imaging in cognitive disorders - from diagnosis to treatment and monitoring].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42157624},
issn = {1652-7518},
mesh = {Humans ; Magnetic Resonance Imaging ; *Neuroimaging/methods ; Tomography, X-Ray Computed ; *Cognition Disorders/diagnostic imaging/therapy/diagnosis ; *Brain/diagnostic imaging/pathology ; Alzheimer Disease/diagnostic imaging/therapy ; Positron-Emission Tomography ; },
abstract = {Brain imaging is essential in the diagnostic workup of cognitive disorders. Computed tomography (CT) is usually the first-line method due to accessibility and patient comfort, whereas magnetic resonance imaging (MRI) offers higher diagnostic precision and is required before anti-amyloid therapy. MRI adds value by detecting microvascular pathology, enabling volumetric analysis, and ensuring safe monitoring of amyloid-related imaging abnormalities (ARIA). National Swedish MRI protocols and structured reporting templates support harmonized diagnostics and follow-up. Nuclear medicine methods are useful for complex cases to assess glucose metabolism, amyloid burden or dopamine transport function. With emerging treatment options for Alzheimer's disease, standardized imaging and close collaboration across specialties are essential for upscaling diagnostic routines and for safe and efficient care.},
}

Humans
Magnetic Resonance Imaging
*Neuroimaging/methods
Tomography, X-Ray Computed
*Cognition Disorders/diagnostic imaging/therapy/diagnosis
*Brain/diagnostic imaging/pathology
Alzheimer Disease/diagnostic imaging/therapy
Positron-Emission Tomography

@article {pmid42157845,
year = {2026},
author = {Bouton, J and Bretteville, A and Tresadern, G and Shaffer, P and Austin, N and Buijnsters, P and Cedervall, EP and Darville, N and Fonteyn, I and Leenaerts, J and Lamenca, CM and Mertens, L and Peeters, D and Velter, AI and Roosbroeck, YV and Ebneth, A and Bartolomé, JM and Trabanco, AA and Oehlrich, D},
title = {Discovery of 5‑Azaindole Inhibitors of O‑GlcNAcase for the Treatment of Alzheimer's Disease and Related Tauopathies.},
journal = {ACS medicinal chemistry letters},
volume = {17},
number = {5},
pages = {1096-1105},
pmid = {42157845},
issn = {1948-5875},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid-β plaque accumulation and intracellular tau neurofibrillary tangles, with tau pathology correlating more closely with cognitive decline. Modulation of tau phosphorylation through the regulation of O-GlcNAcylation, a post-translational modification controlled by O-GlcNAcase (OGA), represents a promising therapeutic strategy. In this study, we report the optimization of a pyrimidine hit identified by high-throughput screening, leading to the discovery and optimization of a novel series of 5-azaindole-based OGA inhibitors. From this series, compound 24 was identified as an in vivo tool candidate that demonstrated a favorable pharmacokinetic profile and measurable brain exposure. Pharmacodynamic studies in murine models demonstrated that compound 24 induced a significant and transient elevation of brain O-GlcNAcylation levels, confirming the in vivo target engagement. These findings underscore the potential of 5-azaindole-based OGA inhibitors as a novel validated chemotype for modulation of O-GlcNAcylation.},
}

@article {pmid42157881,
year = {2026},
author = {Jabbari, S and Zakaria, ZA and de Menezes, IRA and Mohammadi, S},
title = {Rhamnazin attenuates Amyloid β-Peptide (1-42) induced spatial memory impairments by modulation of BDNF-ERK signaling pathway.},
journal = {3 Biotech},
volume = {16},
number = {6},
pages = {200},
pmid = {42157881},
issn = {2190-572X},
abstract = {Rhamnazin (Rham), a natural flavonoid, possesses various medicinal benefits including anti-inflammatory, antioxidant, antiangiogenic, and antibacterial activities. Additionally, Rham showed neuroprotective effects when assessed using the chronic stress-induced cognitive impairment assay. In this intriguing investigation, researchers delved into the working memory and spatial reference memory of Rham, utilizing a rat model of Alzheimer's disease (AD) induced by amyloid β1-42 (Aβ1-42). Administering Aβ1-42 directly into the ventricles led to notable cognitive impairments in behavioral assessments of rats with AD. However, chronic treatment of Rham (30, 60, and 120 mg/kg) once per day during five consecutive days improved the cognitive functions of AD-induced rats in a dose-dependent manner which was not observed following the acute Rham treatment. Concurrently, Rham administration also increased the levels of BDNF and phosphorylated ERK in the hippocampus. Moreover, the cognitive boost triggered by Rham was replicated through the overproduction of BDNF in the hippocampus. However, this effect was thwarted by either the bilateral delivery of lentiviruses expressing BDNF shRNA into the hippocampus or by a targeted injection of an ERK inhibitor. In conclusion, chronic treatment with Rham improves the cognitive deficits in AD-induced rats possibly via the upregulation of BDNF/ERK signaling pathway in hippocampus.},
}

@article {pmid42157911,
year = {2025},
author = {Waqar, Z and Sethi, P and Jain, D and Singh, K and Alsaidan, OA and Alzarea, SI and Gupta, JK and Saxena, S and Sharma, MC},
title = {Precision Medicine in Neurodegenerative Diseases: Genomic Approaches to Target Amyloid-β, Tau, and Alpha-Synuclein Pathways.},
journal = {Current genomics},
volume = {26},
number = {6},
pages = {469-494},
pmid = {42157911},
issn = {1389-2029},
abstract = {Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by the pathological aggregation of proteins such as amyloid-β, tau, and alpha-synuclein. These hallmark proteins play central roles in disease progression and represent promising targets for therapeutic intervention. Advances in precision medicine, driven by genomic technologies such as CRISPR-Cas systems, RNA-based therapies, and high-throughput sequencing, have enabled the development of tailored strategies to modulate these pathological pathways. This review examines the integration of genomic approaches in targeting amyloid-β, tau, and alpha-synuclein, emphasizing their potential to mitigate disease progression and improve patient outcomes. We highlight current progress in preclinical and clinical studies, discuss challenges associated with translating these therapies into clinical practice, and explore future directions for achieving therapeutic precision in neurodegenerative disorders. By examining the interplay of genetic, molecular, and therapeutic innovations, this review underscores the transformative potential of genomic medicine in addressing the unmet needs of neurodegenerative disease treatment.},
}

@article {pmid42157943,
year = {2026},
author = {Li, R and Yao, J and Peng, W and Zheng, L and Wu, X and Shui, X and Zheng, X and Tian, W and Wang, L and Zhou, Y and Ruan, X and Pan, X and Zhang, T and Liu, Y and Lee, TH and Chen, D},
title = {A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.},
journal = {International journal of biological sciences},
volume = {22},
number = {9},
pages = {4724-4746},
pmid = {42157943},
issn = {1449-2288},
mesh = {*Death-Associated Protein Kinases/metabolism/genetics ; Animals ; *Alzheimer Disease/metabolism/drug therapy ; Mice ; Female ; Humans ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; Proteolysis ; Phosphorylation ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. In vivo, upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.},
}

*Death-Associated Protein Kinases/metabolism/genetics
Animals
*Alzheimer Disease/metabolism/drug therapy
Mice
Female
Humans
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
Proteolysis
Phosphorylation

@article {pmid42158156,
year = {2026},
author = {Li, R and Chen, Z and Jiang, Y and Yan, S and He, J and Yan, J and Zong, G and Yi, Z and Ren, X and Jia, B},
title = {Electroacupuncture for treating the cognitive symptoms of Alzheimer's disease: a randomized controlled trial.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1834514},
pmid = {42158156},
issn = {1664-0640},
abstract = {INTRODUCTION: The long-term efficacy of electroacupuncture (EA) in treating cognitive symptoms of Alzheimer's disease (AD) remains unclear, and its time-dependent relationship requires further investigation.

METHODS: Sixty-six patients were allocated to the EA or sham EA group, with stimulation for 20 minutes, for a 24-week treatment period, and were followed-up at 4 weeks. The primary outcome was the mean change in the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) score. Activities of daily living and behavioral and psychological symptoms were also assessed.

RESULTS: After 24 weeks of intervention, patients demonstrated significant improvements in ADAS-Cog scores, with sustained benefits observed during the 4-week follow-up period. In addition, improvements were observed in activities of daily living and behavioral and psychological symptoms.

DISCUSSION: The use of EA as a promising nonpharmacological intervention for AD.

CLINICAL TRIAL REGISTRATION: https://www.chictr.org.cn/showproj.html?proj=151275, identifier (ChiCTR2200056329).},
}

@article {pmid41943055,
year = {2026},
author = {Di Caro, V and Cho, E and Thiel, J and Lizama, BN and Koel-Simmelink, MJA and Pandey, K and Duong, D and Seyfried, NT and Grundman, M and Teunissen, CE and Zetterberg, H and Blennow, K and Caggiano, AO and Hamby, ME},
title = {Impact of zervimesine on the neuroinflammatory biomarker GFAP and related proteomic molecular correlates in plasma of participants from a phase 2 clinical trial in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41943055},
issn = {1758-9193},
support = {1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; 1R01AG058660/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Zervimesine (CT1812) is an investigational brain-penetrant small molecule modulator of the sigma-2 receptor (S2R/TMEM97), currently in clinical development for the treatment of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) that selectively prevents and displaces the binding of amyloid beta (Aβ) and α-synuclein oligomers from neuronal synapses. Given the mechanism of action, it was hypothesized that zervimesine might be more effective in patients with lower levels of AD pathology. Indeed, in the SHINE trial, a completed Phase 2, randomized, double-blind, clinical trial conducted in participants with AD, a robust, 95%, slowing of cognitive decline, as assessed via ADAS-Cog11, was observed in a pre-specified subgroup of participants with lesser AD pathology (i.e., low p-tau217 subgroup) compared to a 38% slowing in the overall modified intent-to-treat (mITT)) population.

METHODS: In SHINE, exploratory plasma biomarkers were assessed using both a targeted and an unbiased, proteomics discovery approach in plasma from participants at baseline and end of study. Treatment effects of zervimesine relative to placebo were assessed in both the mITT population and in a low p-tau217 subgroup, who entered the study with lower (< 1pg/ml) plasma p-tau217 concentrations. Plasma biomarkers Aβ40, Aβ42, GFAP, NfL and BD-tau were assessed using clinically validated targeted assays, along with untargeted TMT-mass spectrometry (MS)-based discovery proteomics followed by bioinformatic, pathway and correlation analyses.

RESULTS: Collectively, plasma biomarker findings in the low p-tau217 subgroup were more robust than in the mITT population. Levels of GFAP were significantly decreased and NfL, Aβ42 and Aβ40 levels trended towards a decrease with zervimesine compared to placebo. Proteomics analyses identified candidate pharmacodynamic biomarkers of zervimesine, and gene ontology and pathway analyses pointed to an impact on amyloid biology, trafficking, lipid metabolism, and immune response. Bioinformatics and correlation analyses with GFAP identified biomarkers that may reflect pathway engagement of S2R and/or decreased neuroinflammation.

CONCLUSIONS: Exploratory plasma biomarker findings align with the degree of clinical benefit in SHINE mITT and low p-tau217 populations, and support future trial enrichment with patients with lower levels of pathology as defined by lower baseline plasma levels of p-tau217.

TRIAL REGISTRATION: July 20th, 2018 ClinicalTrials.gov Identifier NCT03507790 https://clinicaltrials.gov/study/NCT03507790.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02025-4.},
}

@article {pmid42148948,
year = {2026},
author = {Li, X and Xiao, Y and Liu, F},
title = {Stevioside extends the healthspan and improves Alzheimer's disease and increases oxidative stress resistance via the mitochondrial unfolded protein response.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6fo00251j},
pmid = {42148948},
issn = {2042-650X},
abstract = {Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPR[mt]) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPR[mt] pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.},
}

@article {pmid42149381,
year = {2026},
author = {Han, L and Xiong, X and Fan, M and Zhang, L and Gao, S and Li, R and Wang, X and Xiao, X and Huang, C and Yang, J},
title = {Early-Life Psychological Stress Impairs Spatial Learning and Memory in Rats by Altering the Hippocampal Proteome.},
journal = {Behavior genetics},
volume = {},
number = {},
pages = {},
pmid = {42149381},
issn = {1573-3297},
support = {82201342//National Natural Science Foundation of China/ ; xzy022023022//Xi 'an Jiaotong University Basic Research Student Project/ ; 2022PT-07//the Scientific Research and Sharing Platform Construction Project of Shaanxi Province/ ; },
abstract = {Early-life stress has been linked to anxiety, pessimism, and cognitive decline, all of which can have detrimental effects on individuals. One critical structure impacted by early-life stress is the hippocampus, which plays a vital role in regulating learning and memory functions. This study aims to elucidate the molecular mechanisms through which early-life psychological stress (ELPS) affects the learning and memory capabilities of the hippocampus in rats. In this study, ELPS model was applied on juvenile rats for 14 days. To evaluate the spatial learning and memory abilities of rats, the Morris Water Maze (MWM) test was adopted in this study. This study employed two-dimensional gel electrophoresis (2DE) and ultrahigh-performance liquid chromatographic-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOF-MS) techniques to reveal the proteomic map of the rat hippocampus. Subsequently, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and direct protein-protein interaction (PPI) network construction were performed to identify the biological pathways associated with the differentially expressed proteins (DEPs). ELPS treatment induced age-dependent spatial cognitive deficits. In juvenile rats, ELPS caused mild impairments in spatial learning, as reflected by increased escape latency during specific training days, but did not affect spatial memory. In contrast, adult rats exhibited significant and robust impairments in both spatial learning and spatial memory, with longer escape latency across training days, fewer platform crossings, and reduced time and distance in the target quadrant. These findings demonstrate that ELPS-induced cognitive dysfunction is far more pronounced in adult animals, representing persistent and progressive spatial learning and memory deficits. After therapy, 71 proteins were found in the hippocampal region, including 10 DEPs across the juvenile and adult groups post-treatment. Subsequent pathway analysis indicated the involvement of 4 DEPs in various pathways, including Biosynthesis of amino acids, Prion disease, HIF-1 signaling pathway, Distal axon, Alzheimer disease, and Necroptosis pathways. Our study revealed significant proteomic changes in the hippocampus of rats as they transitioned from juveniles to adults, including 10 consistently differentially expressed proteins. These proteomic alterations correspond to the age-dependent spatial cognitive deficits induced by ELPS-mild spatial learning impairment in juveniles and more pronounced deficits in both spatial learning and memory in adults-collectively supporting the lasting effects of ELPS on spatial cognitive function.},
}

@article {pmid42149389,
year = {2026},
author = {Gautam, AS and Singh, RK},
title = {Chrysin Ameliorated Neurochemical and Behavioural Changes Mediated By Combined Exposure of Interleukin-17 A With Amyloid Beta1-42 in Mice.},
journal = {Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology},
volume = {21},
number = {1},
pages = {},
pmid = {42149389},
issn = {1557-1904},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity/administration & dosage ; *Flavonoids/pharmacology/therapeutic use ; Mice ; *Interleukin-17/toxicity/administration & dosage ; Male ; *Peptide Fragments/toxicity/administration & dosage ; Mice, Inbred BALB C ; *Alzheimer Disease/metabolism/chemically induced/drug therapy ; Brain/drug effects/metabolism ; },
abstract = {Neuroinflammation is one of the major hallmarks of neurodegenerative diseases, including Alzheimer's disease (AD). Interleukin-17 (IL-17) cytokine and its downstream signaling have been shown to be implicated in preclinical and clinical models of AD. Moreover, the combination of recombinant IL-17 A with amyloid beta (Aβ1-42) has been shown to be involved in promoting neuroinflammation during AD pathology. Hence, it is speculated that IL-17 may exacerbate Aβ1-42-induced neuronal damage and inflammatory events in the brain. Although natural flavonoids have been reported to protect against neuroinflammation in AD, their role in IL-17 exacerbated Aβ1-42-induced responses has not been reported previously. The current research explored the ability of Chrysin in regulating the exacerbation of neuronal damage and inflammation during AD pathology induced due to the combination of recombinant mouse IL-17 A (rmIL-17 A) with Aβ1-42 in animals. Adult male BALB/c mice were exposed to intranasal Aβ1-42 (5 µg/10µL in phosphate-buffered saline (PBS)/animal) and rmIL-17 (4 µg/kg in 10 µL PBS/animal) from day 1 to day 14 on alternate days with therapeutic oral administration of Chrysin suspension (100 mg/kg) during the last 7 days. Oral treatment with Chrysin demonstrated significant protective effects in improving the memory functions of the animals, along with the modulation of neurodegenerative and neuroinflammatory signalling, microglial and astrocytic activation, and redox balance in the hippocampus and cortex areas of the animal brain tissues. These results supported the neuroprotective ability of Chrysin against the exacerbation caused by rmIL-17 A in Aβ1-42-induced AD in a mouse model.},
}

Animals
*Amyloid beta-Peptides/toxicity/administration & dosage
*Flavonoids/pharmacology/therapeutic use
Mice
*Interleukin-17/toxicity/administration & dosage
Male
*Peptide Fragments/toxicity/administration & dosage
Mice, Inbred BALB C
*Alzheimer Disease/metabolism/chemically induced/drug therapy
Brain/drug effects/metabolism

@article {pmid42149841,
year = {2026},
author = {Guu, TW and Li, WJ and Lee, SH and Hsu, CS and Chou, CN and Lack, L and Ma, WF},
title = {Facilitating the measurement and treatment of Behavioral and Psychological Symptoms of Dementia (BPSD) and understanding caregiver burden using wearable devices in Rural Taiwan-Protocol for a dyadic feasibility pilot study.},
journal = {PloS one},
volume = {21},
number = {5},
pages = {e0342136},
pmid = {42149841},
issn = {1932-6203},
mesh = {Humans ; Pilot Projects ; *Caregivers/psychology ; Taiwan ; *Wearable Electronic Devices ; *Dementia/psychology/therapy ; Female ; Male ; Feasibility Studies ; Aged ; Quality of Life ; Surveys and Questionnaires ; Rural Population ; Alzheimer Disease/psychology ; Middle Aged ; Depression ; *Caregiver Burden/psychology ; Actigraphy ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevalence rises with societal ageing. In clinical care, behavioral and psychological symptoms of dementia (BPSD)-including depression, agitation/aggression, apathy, and sleep disturbance-worsen patients' quality of life and substantially increase caregiver burden, more significantly than the cognitive symptoms. Standard BPSD assessments rely on caregiver-rated questionnaires that are cross-sectional and may be biased when caregivers are themselves older adults. Device-based measures (e.g., research-grade wrist actigraphy) can provide objective longitudinal data and novel features. In parallel, therapeutic wearables may improve sleep and mood in adults, and might improve BPSD if accepted by people living with dementia.

METHODS: This dyadic pilot study will recruit 20 participants (n = 10 AD patients; n = 10 caregivers) from outpatient services and affiliated day-care/dementia hubs in rural Taiwan. Participants will wear Geneactiv continuously for 8 weeks and Re-Timer ≥30 min/day for 4 weeks. Device-based data will be processed with GGIR, a well validated R-package designed for processing accelerometer data. Questionnaire assessments include Pittsburgh Sleep Quality Index (PSQI), Neuropsychiatry Inventory Questionnaire (NPI-Q), Caregiver Burden Inventory (CBI), and a semi-structured interview based on the Taiwanese version of Quebec User Evaluation of Satisfaction with Assistive Technology (T-QUEST) at prespecified timepoints.

DISCUSSION: Wearable devices may facilitate the measurement and treatment of specific BPSD, as well as reduce caregiver burden. If proven feasible even in rural Taiwan where both digital and health literacy and resources are limited, this model will inform how device-based dementia care model can be considered and applied in the context of global ageing.},
}

Humans
Pilot Projects
*Caregivers/psychology
Taiwan
*Wearable Electronic Devices
*Dementia/psychology/therapy
Female
Male
Feasibility Studies
Aged
Quality of Life
Surveys and Questionnaires
Rural Population
Alzheimer Disease/psychology
Middle Aged
Depression
*Caregiver Burden/psychology
Actigraphy

@article {pmid42151713,
year = {2026},
author = {Stijven, F and Mallinckrodt, C and Molenberghs, G and Alonso, A and Dickson, SP and Hendrix, SB},
title = {Time-Scale Target Parameters and Two-Step Estimation in Longitudinal Trials for Progressive Diseases.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70591},
doi = {10.1002/sim.70591},
pmid = {42151713},
issn = {1097-0258},
support = {//Agentschap Innoveren en Ondernemen/ ; HBC.2022.0145//Johnson & Johnson Innovative Medicine/ ; },
mesh = {Humans ; *Disease Progression ; Longitudinal Studies ; Alzheimer Disease/drug therapy/therapy ; *Randomized Controlled Trials as Topic/statistics & numerical data/methods ; Computer Simulation ; Models, Statistical ; Time Factors ; Treatment Outcome ; Data Interpretation, Statistical ; },
abstract = {In progressive diseases such as Alzheimer's, treatments that slow progression should start early to preserve higher levels of functioning for a longer period. In corresponding clinical trials, treatment effects are usually expressed as mean differences on a clinical scale at fixed time points. Early in the disease course, however, these mean differences may appear small but may nonetheless correspond to an important slowing of disease progression. This complicates the appreciation of the relevance of observed treatment effects. We introduce a class of target parameters that quantify treatment effects on the time scale in longitudinal studies; for instance, in terms of time saved or percentage slowing of progression. We focus on data from randomized trials where the target parameters are identified under regularity assumptions. These target parameters remain well defined if treatment was not randomized, but additional untestable assumptions are required for identification. We propose general two-step estimators. In the first step, the data can be analyzed with standard methods for longitudinal data and standard software can thus be used. In the second step, summary statistics from the first step are used for inferences about the target parameters. The second step has been implemented in the TCT R package. We study the asymptotic properties and efficiency of these two-step estimators, and evaluate them in an extensive simulation study. These estimators are used in a phase 2/3 clinical trial for Alzheimer's disease, leading to important additional insights into the treatment effect.},
}

Humans
*Disease Progression
Longitudinal Studies
Alzheimer Disease/drug therapy/therapy
*Randomized Controlled Trials as Topic/statistics & numerical data/methods
Computer Simulation
Models, Statistical
Time Factors
Treatment Outcome
Data Interpretation, Statistical

@article {pmid42151732,
year = {2026},
author = {Hammers, DB and Foster, E and Eloyan, A and Thangarajah, M and Taurone, A and Touroutoglou, A and La Joie, R and Beckett, L and Gao, S and Vemuri, P and Nudelman, KN and Kirby, K and Dage, JL and Aisen, P and Atri, A and Clark, D and Day, GS and Duara, R and Graff-Radford, NR and Grant, I and Honig, LS and Johnson, ECB and Jones, DT and Masdeu, JC and Mendez, MF and Parand, L and Womack, K and Musiek, E and Onyike, CU and Riddle, M and Rogalski, E and Salloway, S and Sha, SJ and Turner, RS and Wingo, TS and Wolk, DA and Dickerson, BC and Rabinovici, GD and Carrillo, MC and Apostolova, LG and , },
title = {Cognitive dispersion profiles and prediction of cognitive change in early-onset dementias: Results from LEADS.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71492},
doi = {10.1002/alz.71492},
pmid = {42151732},
issn = {1552-5279},
support = {AARG-22-926940/ALZ/Alzheimer's Association/United States ; LDRFP-21-818464/ALZ/Alzheimer's Association/United States ; K23 AG080071/ALZ/Alzheimer's Association/United States ; R56 AG057195/ALZ/Alzheimer's Association/United States ; U01AG6057195/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; U01 AG016976/ALZ/Alzheimer's Association/United States ; P30 AG010133/ALZ/Alzheimer's Association/United States ; P50 AG008702/ALZ/Alzheimer's Association/United States ; P50 AG025688/ALZ/Alzheimer's Association/United States ; P50 AG005146/ALZ/Alzheimer's Association/United States ; P30 AG062421/ALZ/Alzheimer's Association/United States ; P30 AG062422/ALZ/Alzheimer's Association/United States ; P50 AG023501/ALZ/Alzheimer's Association/United States ; P30 AG010124/ALZ/Alzheimer's Association/United States ; P30AG066506/ALZ/Alzheimer's Association/United States ; P30 AG013854/ALZ/Alzheimer's Association/United States ; P50 AG005681/ALZ/Alzheimer's Association/United States ; P50AG047366/ALZ/Alzheimer's Association/United States ; U24AG021886/ALZ/Alzheimer's Association/United States ; R56AG057195/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Male ; Neuropsychological Tests/statistics & numerical data ; *Dementia/psychology ; *Cognition/physiology ; Biomarkers ; Middle Aged ; *Alzheimer Disease/psychology ; Age of Onset ; },
abstract = {INTRODUCTION: Research into cognitive dispersion - a cognitive process score measuring the intra-individual variability (IIV) across a single testing session - suggests utility in neurodegenerative populations. Given widespread deficits observed in sporadic early-onset Alzheimer's disease (EOAD), however, it is unclear if examining cognitive dispersion shows benefit in this condition.

METHODS: A total of 309 participants (188 amyloid-positive EOAD, 43 amyloid-negative early-onset dementia [EOnonAD], 78 cognitively normal [CN]) completed neuropsychological testing twice over 12 months. Dispersion-related differences among groups were assessed, as was cognitive dispersion's capacity to predict domain-specific cognitive trajectories, and its convergence with imaging biomarkers.

RESULTS: EOAD participants displayed higher cognitive dispersion than EOnonAD participants, and associations with EOAD-specific biomarkers. Additionally, cognitive dispersion was associated with 12-month reliable change across several cognitive domains.

DISCUSSION: These preliminary results examine cognitive dispersion in sporadic EOAD. When used with baseline cognitive performance, cognitive dispersion measures may enrich future clinical trials in EOAD by enhancing treatment monitoring over time.},
}

Humans
Female
Male
Neuropsychological Tests/statistics & numerical data
*Dementia/psychology
*Cognition/physiology
Biomarkers
Middle Aged
*Alzheimer Disease/psychology
Age of Onset

@article {pmid42151912,
year = {2026},
author = {Stuardo, N and Cáceres-Quezada, Á and Guzmán, D and Lamaizon, CM and Leal R, N and Koleske, AJ and Álvarez R, A},
title = {Abl kinase activation promotes axon initial segment disassembly and protein sorting defects in Alzheimer's disease.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02624-5},
pmid = {42151912},
issn = {1741-7007},
abstract = {BACKGROUND: Axon initial segment (AIS) dysfunction disrupts neuronal compartmentalization, which leads to pathological processes like Tau missorting in Alzheimer's disease (AD). However, the molecular mechanisms that destabilize the AIS scaffold are incompletely understood. Our group has previously shown that the Abl1 non-receptor tyrosine kinase is aberrantly activated in AD mouse models and promotes dendritic spine collapse, Tau hyperphosphorylation, and neuronal apoptosis. Given the important role of Abl1 in AD and its emerging significance in Tau pathology, we examined how it contributes to AIS collapse.

RESULTS: We find that activation of Abl1 by amyloid-β fibrils promotes AIS disruption, as determined by the loss of clustered AnkG in the proximal axon, and that this can be prevented by pharmacological inhibition of Abl kinases. Cytosolic extraction experiments show that active Abl1 associates to the AIS scaffold, and this association increases in response to amyloid-β fibril treatment. Furthermore, using expansion microscopy, we show that Abl1 localizes to the AIS in dissociated hippocampal cultures and in mouse brain slices. We find a decrease in AIS actin patches, key for maintenance of neuronal compartmentalization, following Abl kinase activation. Finally, we show that Abl1 activation promotes missorting of somatodendritic Rab11 into the axon and the axonal protein Tau into the somatodendritic compartment, indicating a bidirectional failure in AIS barrier function.

CONCLUSIONS: Taken together, our results show that Abl1 plays an important role in AIS destabilization and that its activation compromises protein compartmentalization in a primary neuron culture model of AD.},
}

@article {pmid42151941,
year = {2026},
author = {Luo, M and Zhao, FK and Wang, YM and Bian, J and Luo, Y},
title = {Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04529-5},
pmid = {42151941},
issn = {1477-3155},
support = {Zunyi Science and Technology Talent Team Project [2024] No. 6//Zunyi Science and Technology Bureau/ ; No. 39 (2023)//Zunshi Science and Technology Cooperation Letter/ ; (QZYY-2024-094)//Science and technology research topic of traditional Chinese medicine and ethnic medicine of Guizhou Provincial Administration of Traditional Chinese Medicine/ ; No: 24QNMP019//Health Commission of Sichuan Province Medical Science and Technology Program/ ; 25MSZX259//Scientific Research Projects of the Sichuan Provincial Administration of Traditional Chinese Medicine/ ; 2026NSFSC1634//Sichuan Province Natural Science Foundation/ ; },
abstract = {Nanomaterials have demonstrated substantial promise in the diagnosis and treatment of neurological and psychiatric disorders, offering novel strategies to overcome the limitations of traditional therapies. This review utilizes bibliometric analysis to evaluate global trends in nanomaterial research for neurological and psychiatric diseases, based on a corpus of 3,987 publications retrieved from the Web of Science Core Collection spanning from 1997 to August 2025. The analysis reveals a consistent upward trajectory in annual publications, reflecting substantial and growing international interest across diverse regions. Following an overview of global research dynamics, this review explores the pathogenesis of neurological and psychiatric disorders, such as Alzheimer's disease, Parkinson's disease, depression, and schizophrenia. The mechanisms underlying these conditions, including neuroinflammation, oxidative stress, protein aggregation, and neurotransmitter imbalances, are systematically discussed. Subsequently, the review focuses on how nanomaterials, including nanoparticles, nanocomposites, and nanocarriers, target these pathogenic mechanisms. The therapeutic applications of nanomaterials are evaluated with respect to their ability to modulate neuroinflammation, reduce oxidative stress, improve drug delivery to the brain, and facilitate the repair of neuronal damage. Despite the promising potential of nanomaterials, several challenges remain, including biocompatibility, targeted delivery, and scalability of treatment options. The review concludes by highlighting future directions for research, emphasizing the need for continued innovation in nanomaterial design and application to address these challenges and advance clinical treatments for neurological and psychiatric disorders.},
}

@article {pmid42152119,
year = {2026},
author = {Skácelíková, E and Vyhnálek, M and Děchtěrenko, F and Nikolai, T and Veverová, K},
title = {Willingness and barriers to blood-based biomarker testing of Alzheimer's disease in the general population in the Czech Republic.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02070-z},
pmid = {42152119},
issn = {1758-9193},
support = {PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; PTC-Gene-25-1439553//Alzheimer's Association - Part the Cloud Translational Research Program/ ; CZ.02.01.01/00/22_008/0004595//European Regional Development Fund, under the project "Beyond Security: Role of Conflict in Resilience-Building"/ ; },
abstract = {BACKGROUND: Blood-based biomarkers (BBBM) for Alzheimer's disease (AD) are entering clinical practice with new clinical practice guidelines and the first FDA-approved blood test. Their implementation will depend not only on assay performance but also on public willingness, trust, and understanding of probabilistic results. We examined attitudes towards BBBM in the general population and psychosocial factors that may facilitate or hinder uptake.

METHODS: We conducted an online cross-sectional survey among adults aged ≥ 35 years (M = 51.08, SD = 9.79) in the Czech Republic (N = 666). The survey assessed willingness to undergo BBBM testing, sociodemographic characteristics, experience with AD, depressive symptoms (Patient Health Questionnaire, PHQ-9), concerns about developing AD, and medical distrust (Medical Distrust Index, MDI). Logistic regression models (unweighted and weighted for gender and region) were estimated to examine the association with willingness. Open-ended responses were analyzed thematically to identify motivators and barriers.

RESULTS: Overall, 92.8% of participants reported that they would undergo BBBM testing. Greater concern about developing AD was the strongest facilitator (OR = 1.59-2.34). Having AD in a close family member was associated with lower willingness (OR = 0.31-0.43), as was higher medical distrust (MDI OR = 0.79 in the fully weighted model). Education, age, gender, depressive symptoms, and AD knowledge were not significantly associated with willingness. Qualitative analyses showed that participants viewed BBBM as a way to "take action in time", "know one's health status" and "prepare for the future", whereas fear of AD, preference "not to know", perceived lack of treatment, test uncertainty/"only probability", and privacy concerns were common barriers.

CONCLUSIONS: Public willingness to undergo BBBM testing is high, but psychosocial barriers, particularly familial experience of AD and medical distrust, may limit real-world uptake. Addressing these barriers through targeted education, probabilistic risk communication, and trusted primary-care pathways will be essential for the responsible implementation of BBBM in clinical practice.},
}

@article {pmid42142451,
year = {2026},
author = {Razavi, A and Hou, J and Lin, SJ and Zhang, C and Kremen, WS and Fennema-Notestine, C and Elman, J and Holmans, P and Faraone, SV and Gaiteri, C and Hess, JL and Glatt, SJ},
title = {Predicted brain-regional gene expression patterns in individuals living with Alzheimer's disease.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {29-40},
doi = {10.1016/j.neurobiolaging.2026.04.006},
pmid = {42142451},
issn = {1558-1497},
abstract = {Studying brain gene expression in Alzheimer's Disease (AD) remains difficult as postmortem brain is difficult to access, cannot be used to guide donor treatment, may be confounded by environmental factors before and after death, and is difficult to link to early AD states or disease progression. To circumvent these limitations, several studies have tested blood transcriptome biomarkers for AD. However, gene-expression levels in the blood have limited correlation with those in the brain. To evaluate the potential of monitoring Alzheimer's progression with peripheral data, we used transcriptome-imputation to identify brain-region-specific AD-associated gene-expression differences in cohorts with blood-based transcriptome data. This approach provides a high-resolution image of AD-associated molecular differences in the brains of individuals actively living with disease. We analyzed eight AD studies (777 AD cases, 779 cognitively unimpaired controls), imputing transcriptomes in 10 brain regions via the Brain Gene Expression and Network Imputation Engine (BrainGENIE). Hundreds of differentially expressed genes (DEGs) associated with AD were identified in nine brain regions, with anterior cingulate cortex and amygdala showing the most differential expression. AD-associated genes were enriched in pathways such as proteostasis, mitochondrial dysfunction, and immune activation. We observed significant yet moderate concordance between imputed AD-associated changes and those directly measured in the dorsolateral prefrontal cortex and cerebellum. These transcriptomic changes can guide future in vitro studies focused on pathogenesis or be targets of novel therapeutic development. In conclusion, we demonstrated the scope and utility of brain expression imputation from the peripheral transcriptome, laying the groundwork for biomarker discovery and prospective AD studies.},
}

@article {pmid42142620,
year = {2026},
author = {Shang, X and Chen, SY and Zhang, XY and Regina, I and Zhang, T and Luo, J and Yan, YZ and Qiao-yuanYao, and Tong, F and Pan, LH},
title = {Insulin in brain: The physiological functions and therapeutic insights for neurodegenerative diseases.},
journal = {Life sciences},
volume = {398},
number = {},
pages = {124468},
doi = {10.1016/j.lfs.2026.124468},
pmid = {42142620},
issn = {1879-0631},
abstract = {This review highlight the function of insulin in the central nervous system in addition to its role in the periphery. The cerebral distribution and mechanisms of insulin and its receptor isoforms are reviewed in detail. We emphasize the essential roles of insulin in the maintenance of cerebral glucose homeostasis, modulation of cognitive performance, regulation of appetite, promotion of cerebrovascular angiogenesis, and exertion of neuroprotective effects. We demonstrate how insulin resistance exacerbates characteristic neuropathological features in Alzheimer's disease (AD) and Parkinson's disease (PD), while insulin-based interventions ameliorate these pathologies through multiple mechanisms including increasing the activity of insulin-degrading enzyme, suppressing Aβ neurotoxicity, and reducing α-synuclein deposition. The review also systematically examines the neuroprotective effects of insulin sensitizers and their potential to reduce the risk of AD, while noting the complexity of their bidirectional regulatory role in PD, which warrants further investigation. Notably, intranasal insulin administration emerges as a promising non-invasive therapeutic approach that bypasses the blood-brain barrier via olfactory and trigeminal pathways, suggesting significant potential for cognitive enhancement and neuropathological mitigation. Nonetheless, it must be noted that the optimal dosage, long-term safety, and sustained efficacy of insulin therapy remain unclear, and the current evidence is derived primarily from preclinical studies or small-scale clinical trials. In summary, this review paper underscores the critical physiological roles of insulin in the brain and outlines novel therapeutic strategies for using insulin in the treatment of AD and PD.},
}

@article {pmid42142765,
year = {2026},
author = {Feng, Y and Zhang, C and Wei, Y and Liu, E and Sun, H and Flatt, P and Gault, V and Irwin, N and Hölscher, C and Hao, L and Zhang, Z},
title = {A novel bifunctional peptide predicted to target neuropeptide Y4 and GLP-1 receptors alleviates cognitive deficits in 5 × FAD mice by modulating cGAS-STING-mediated neuroinflammation.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {118074},
doi = {10.1016/j.bcp.2026.118074},
pmid = {42142765},
issn = {1873-2968},
abstract = {Effective disease-modifying therapies for Alzheimer's disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo, NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden (P < 0.05), alleviated neuronal injury (P < 0.01), improved synaptic integrity (P < 0.01), and attenuated mitochondrial abnormalities (P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) (P < 0.05), cGAS (P < 0.05), STING (P < 0.05), and phosphorylated IRF3 (P < 0.01), together with decreased IL-1β (P < 0.05) and increased IL-10 (P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling (P < 0.05) and inflammatory responses (P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.},
}

@article {pmid42143322,
year = {2026},
author = {Gröbner, LS and Pietrzik, CU},
title = {Transport pathways across the blood-brain barrier for waste clearance and drug delivery.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00812-7},
pmid = {42143322},
issn = {2045-8118},
abstract = {The blood-brain barrier (BBB) displays a highly organized and complex structure, which is important for maintaining brain homeostasis and protecting the brain from foreign molecules or pathogens. Receptor-mediated transcytosis (RMT) is one of the main delivery pathways across the BBB for molecules that cannot pass the barrier via, e.g. paracellular diffusion. For understanding the treatment options in neurodegenerative diseases such as Alzheimer´s disease (AD), it is important to investigate transport pathways and mechanisms at the BBB for a potential delivery of drugs, antibodies or other compounds across the BBB. This review provides an overview of the different transport variants across the BBB and how they can be targeted in order to promote internalization or secretion into or out of the brain. Therefore, we want to focus on two characterized proteins: the low-density lipoprotein receptor-related protein 1 (LRP1), which is a key mediator of amyloid β (Aβ) clearance from the brain during AD, and transferrin receptor 1 (TfR1), which is already used as a target for antibody-delivery into the brain. Additionally, this review discusses two other important proteins, which have been less frequently addressed in research regarding transport mechanisms: P-glycoprotein (P-gp) as another transporter at the BBB and proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-known regulator of cholesterol homeostasis which promotes the degradation of the low-density lipoprotein receptor (LDLR) and LRP1. For these four main proteins, we aim to highlight existing approaches for targeting or inhibiting the aforementioned receptors or proteins. The approaches enable a higher penetration of the BBB, a better distribution in the brain, and ultimately fewer side effects of antibodies or nanoparticles. Here, we include lecanemab, trontinemab, dual TfR/CD98hc shuttles, evolocumab and alirocumab, immunoliposomes and other nanoparticles targeting TfR1 or LRP1. We will further highlight approaches which differ from these common ideas and demonstrate the current state of the art regarding drug delivery and waste clearance across the BBB.},
}

@article {pmid42144109,
year = {2026},
author = {Loukil, I and Vachon, A and Çaku, A and Plourde, M},
title = {Krill oil increase plasma omega-3 fatty acids more than fish oil in healthy adults: a double blind randomized controlled trial.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.ajcnut.2026.101346},
pmid = {42144109},
issn = {1938-3207},
abstract = {BACKGROUND: Omega-3 fatty acids (ω-3 FAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are recognized for their health benefits. However, their circulating levels after supplementation may be modulated by several factors, including sex, carriage of the apolipoprotein E4 allele (APOE4), and the chemical form of the supplement. Krill-oil delivers ω-3 FAs primarily as phospholipids (PL), whereas fish oil provides them as triglycerides (TG).

OBJECTIVE: To compare EPA and DHA concentrations after a supplementation with krill oil and fish oil and assess whether sex and APOE4 genotype modifies responses to supplementation.

METHODS: This double-blind, randomized clinical trial included 72 healthy adults (53 females, 19 males) matched for age and body mass index (BMI). Participants received 1.1 g/day ω-3 FAs through either krill oil (n=36) or fish oil (n=36) for 12 weeks. Plasma fatty acids were measured at baseline and at weeks 1, 2, 4, and 12 by gas chromatography-flame ionization detection. Differences in plasma ω-3 FAs concentrations by treatment, sex and APOE4 status, were analyzed.

RESULTS: Time-by-treatment interactions were significant for plasma delta over baseline concentrations of EPA (p = 0.0001) and DHA (p = 0.005), with krill oil resulting in ∼ 1.5-fold higher ΔEPA and ΔDHA compared to fish oil. The time-by-sex interaction was significant only for EPA (p = 0.026), with females having 1.5-fold greater increase than males at 12 weeks. Following supplementation with either krill oil or fish oil, APOE4 carriers had 3-fold and 1.6-fold higher EPA and DHA respectively, compared to baseline; however, these increases were not significantly different from those found in non-carriers.

CONCLUSIONS: Krill oil increased plasma ω-3 FAs more than fish oil, regardless of APOE4 genotype. Individuals with higher ω-3 FA requirements may achieve adequate enrichment with lower doses of krill oil compared to fish oil supplementation.

REGISTRATION NUMBER: NCT04279743. In https://clinicaltrials.gov.},
}

@article {pmid42144687,
year = {2026},
author = {Zhao, Q and Yu, Y and Wang, F and Wang, Y and Shao, P and Zhao, L},
title = {TARDBP Mediates the MAP3K11/SLC3A2/GPX4 Axis in Alzheimer's Disease Rats by Enhancing KRAS mRNA Stability.},
journal = {Journal of cellular and molecular medicine},
volume = {30},
number = {10},
pages = {e71181},
doi = {10.1111/jcmm.71181},
pmid = {42144687},
issn = {1582-4934},
support = {HAB202113//Huai'an Natural Science Research Program/ ; },
mesh = {Animals ; Rats ; *Alzheimer Disease/metabolism/genetics/pathology ; PC12 Cells ; *RNA Stability/genetics ; *Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics ; *Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Male ; Hippocampus/metabolism/pathology ; Disease Models, Animal ; Ferroptosis/genetics ; Amyloid beta-Peptides ; Reactive Oxygen Species/metabolism ; Iron/metabolism ; RNA, Messenger/genetics/metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; },
abstract = {Ferroptosis is an emerging pathological mechanism in Alzheimer's disease (AD). The aim of the present study was to investigate the potential mechanisms by which TARDBP is involved in AD by promoting ferroptosis. An AD rat model was established by injecting homocysteine (Hcy). Memory function was assessed using the Morris water maze test and contextual fear conditioning test. Hippocampal neurons' morphology was observed by HE staining, and intracellular iron deposition in the hippocampus was evaluated by Perls' blue staining. PC12 cells were treated with 20 μM Aβ1-42 to establish an AD cell model in vitro. Cell viability was measured by MTT assay; LDH release, intracellular ROS levels and Fe[2+] concentrations were determined. The mRNA stability of KRAS was assessed by actinomycin D assay. Activation of the MAP3K11/SLC3A2/GPX4 pathway was assessed by Western blot. Treatment with Fer-1 or down-regulation of TARDBP improved memory function and reduced intracellular iron deposition in the hippocampus of AD rats. Furthermore, these interventions inhibited Aβ1-42-induced PC12 cell damage, ROS production and iron accumulation. Mechanistically, down-regulating TARDBP reduced the mRNA stability of KRAS, inhibited MAP3K11 expression and subsequently promoted the expression of SLC3A2 and GPX4. Conversely, up-regulation of KRAS reversed the protective effects induced by TARDBP knockdown in both AD rats and Aβ1-42-induced PC12 cells. TARDBP promotes the development of AD by enhancing the mRNA stability of KRAS, thereby mediating the MAP3K11/SLC3A2/GPX4 axis to induce ferroptosis.},
}

Animals
Rats
*Alzheimer Disease/metabolism/genetics/pathology
PC12 Cells
*RNA Stability/genetics
*Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism/genetics
*Proto-Oncogene Proteins p21(ras)/genetics/metabolism
Male
Hippocampus/metabolism/pathology
Disease Models, Animal
Ferroptosis/genetics
Amyloid beta-Peptides
Reactive Oxygen Species/metabolism
Iron/metabolism
RNA, Messenger/genetics/metabolism
Rats, Sprague-Dawley
Signal Transduction

@article {pmid42145109,
year = {2026},
author = {Saxena, P and Kothiyal, P and Ratan, P},
title = {Evaluation of neuroprotective effects of Pyracantha crenulata (D. Don) M. Roem against aluminium chloride induced memory impairment of rats.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/01616412.2026.2673060},
pmid = {42145109},
issn = {1743-1328},
abstract = {Pyracantha crenulata, traditionally used in Himalayan folk medicine, valued for enhancing vitality, mental clarity, and combating age-related cognitive decline due to its antioxidant constituents.

AIM: This study evaluated the neuroprotective effect of hydroalcoholic extract of P. crenulata against aluminium chloride (AlCl3)-induced Alzheimer's disease in rats.

MATERIALS AND METHODS: Alzheimer's pathology was induced using AlCl3, and rats were treated with P. crenulata extract (250 and 500 mg/kg) for 21 days. Cognitive and behavioural performance were assessed using the Morris Water Maze (MWM) and Elevated Plus Maze (EPM). Biochemical parameters, including oxidative stress markers (SOD), cholinesterase activity (AChE), and myeloperoxidase levels (MPO), were measured. Histopathological examination of the hippocampus and cerebral cortex was conducted.

RESULTS: Aluminium intoxication led to marked deficits in learning and memory, as evidenced by performance in the Morris Water Maze and Elevated Plus Maze tests. Treatment with P. crenulata extract significantly enhanced spatial and long-term memory in a dose-dependent manner, with the higher dose producing the most pronounced improvement.

CONCLUSION: The findings of this study highlight the notable neuroprotective effects of P. crenulata, demonstrated through modulation of biochemical parameters and suppression of amyloid precursor protein and Tau, key pathological hallmarks of Alzheimer's disease, further validated by histopathological evidence.},
}

@article {pmid42145110,
year = {2026},
author = {Wimo, A and Jönsson, L},
title = {[Health economic aspects of dementia].},
journal = {Lakartidningen},
volume = {123},
number = {},
pages = {},
pmid = {42145110},
issn = {1652-7518},
mesh = {Humans ; *Dementia/economics/diagnosis/epidemiology ; Sweden/epidemiology ; Cost-Benefit Analysis ; Health Care Costs ; Cost of Illness ; Quality of Life ; Alzheimer Disease/economics ; Life Expectancy ; },
abstract = {The societal costs of dementia in Sweden are very high: about SEK 90-100 billion per year. A purely demographic projection to 2050 gives a cost increase of about 80%. In addition to the costs, dementia also entails a loss of life expectancy for those with dementia and of quality of life for those affected and their relatives. At present, it is not possible to assess whether the antibody treatment against Alzheimer's disease is cost-effective in Sweden because no price is yet available. Blood-based biomarkers for Alzheimer's disease and other diagnostic methods, if included in the pricing basis for new drugs, can be a valuable addition to cost-effectiveness analyses.},
}

Humans
*Dementia/economics/diagnosis/epidemiology
Sweden/epidemiology
Cost-Benefit Analysis
Health Care Costs
Cost of Illness
Quality of Life
Alzheimer Disease/economics
Life Expectancy

@article {pmid42145619,
year = {2026},
author = {Sherva, R and Bayly, H and Zhang, R and Harrington, K and Mez, J and Miller, MW and Tsuang, D and Wolf, E and Zeng, Q and Le Guen, Y and Tejeda, M and , and , and , and Gaziano, JM and Panizzon, MS and Hauger, RL and Merritt, VC and Farrer, LA and Logue, MW},
title = {A Genome-wide Association Study of Alzheimer's Disease and Dementia in a Large Multi-ancestry Military Cohort Identifies Many New Dementia-Associated Loci.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.01.26352216},
pmid = {42145619},
abstract = {INTRODUCTION: Biobank-scale cohorts of individuals with genetic data and diagnoses of Alzheimer's disease and related dementias (ADRD) have facilitated the discovery of additional risk loci via meta-analysis, with existing cohorts assembled specifically for ADRD genetic discovery. Cross-ancestry meta-analyses have further elucidated the overall genetic architecture of these dementias. Here, we include for the first time the European ancestry (EA) and Hispanic ancestry (HA) subset of the VA Million Veterans Program (MVP) along with the African ancestry (AA) MVP participants in a meta-analysis with a large-scale EA and AA meta-analysis.

METHODS: Independent genome-wide association studies (GWASs) were conducted in MVP participants using four phenotypes derived from electronic medical records and surveys: ADRD, prescriptions for common dementia medications, and self-reported maternal and paternal history of dementia (dementia by proxy). These GWASs were repeated in the EA, AA, and HA cohorts. MVP ancestry-specific and cross-ancestry meta-analyses were conducted. These were then meta-analyzed with existing GWAS results. Functionality of the peak variants was explored using brain-derived gene expression data and co-localization analysis.

RESULTS: Apart from the APOE region, 17, 4, and 3 genome-wide significant (GWS) loci were observed in the MVP EA, AA, and HA meta-analyses, respectively. When we meta-analyzed these with consortium results, we observed 72 loci in the EA GWAS, and 62 lead loci in the cross-ancestry meta-analysis. While most of these loci were known, 27 genes/regions were identified containing variants surpassing genome-wide significance for the first time: 7 EA specific, 12 in the cross-ancestry meta-analysis, and 8 driven by AA and HA cohorts. Several of these are members of pathways containing established ADRD risk genes, and several of the peak SNPs showed evidence for eQTL effects on their respective genes. Several of the novel SNPs showed significant eQTL effects in brain-derived mRNA-seq experiments. Additionally, there was a significant differential expression of the novel gene PAX7 in ADRD cases and controls.

DISCUSSION: MVP represents a large and unique primarily male cohort comprised of US Veterans from a range of backgrounds with a unique set of environmental exposures. The results generated here demonstrate the utility of biobank level cohorts for AD genetic discovery. Furthermore, our discovery of ADRD genes was enhanced by the inclusion of MVP data that provided an increase of underrepresented ancestry groups in contrast to prior cross ancestry GWASs. The new AD risk loci identified present potential new targets for dementia treatment confirmed that future large-scale analyses of AD genetic risk and prediction will be enhanced by the inclusion of MVP data.},
}

@article {pmid42145636,
year = {2026},
author = {Lorenzi, M and Custo, A and Frisoni, GB and Garibotto, V},
title = {A data-driven Alzheimer's disease progression simulator for retrospective validation and prospective Phase III power design.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.03.26352317},
pmid = {42145636},
abstract = {Anti-amyloid immunotherapies have recently demonstrated the first significant slowing of cognitive decline in Alzheimer's disease (AD), yet clinical benefit varies markedly across drugs and scales with the completeness of amyloid clearance. Pharmacokinetic/pharmacodynamic (PK/PD) models are currently the standard tool for trial simulation, but they typically operate on single biomarkers and rely on drug-concentration assumptions, leaving the multi-scale cascade from amyloid clearance through tau, neurodegeneration, and cognition largely unmodelled. No existing framework has been jointly validated against the quantitative outcomes of multiple real-world phase III trials, spanning clearance kinetics, multi-modal biomarker trajectories, and statistical power. We present a trial simulation platform based on SimulAD, a disease progression model trained exclusively on longitudinal observational data from ADNI, with no access to trial-arm labels or drug-specific outcomes. SimulAD encodes intervention as piecewise amyloid clearance terms within a latent ordinary differential equation system that jointly governs amyloid, tau, structural MRI, and cognitive trajectories under the amyloid cascade hypothesis. We retrospectively simulated six landmark phase III anti-amyloid trials (TRAILBLAZER-ALZ2, CLARITY AD, EMERGE and ENGAGE, GRADUATE I and GRADUATE II) using a single trained model with trial-specific calibration limited to amyloid clearance kinetics. SimulAD reproduced published mean centiloid reductions within 5% error across all six trials and generated CDR-SB distributions broadly consistent with reported placebo and treated-arm outcomes. In a retrospective power analysis, calibrated simulations separated the three positive from the three null trials, with EMERGE near the decision boundary and ENGAGE and both GRADUATE trials below it. Across trials, higher amyloid-clearance rates were associated with larger calibrated clinical effects and lower estimated sample sizes. These results establish SimulAD as a valid disease-progression-centric trial simulator providing quantitative guidance on sample size planning and treatment kinetics optimisation that is grounded in the full multi-modal biomarker cascade of AD.},
}

@article {pmid42146610,
year = {2026},
author = {Shiferaw, TG and Sarkar, S and Baker, KM and Wooldridge, RS and Binfet, HM and Prozapas, VN and Ogbu, CP and Schepmoes, AA and Attah, IK and Niemeyer, CS and Sprenger, KG and Hassell, JE and Eckel, RH and Melchior, JT and Bruce, KD},
title = {ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.05.04.722733},
pmid = {42146610},
issn = {2692-8205},
abstract = {INTRODUCTION: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.

METHODS: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.

RESULTS: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.

DISCUSSION: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.},
}